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ImmunologyThese notes were made by Hadley Wickham, [email protected] and are licensed under the Creative Commons NonCommercial-ShareAlike License. To view a copy of this license, visit http://creativecommons.org/licenses/nc-sa/1.0/ or send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, California 94305, USA.
Table of ContentsOverview of Immunity and Immune System....................................................................3
How Ag’s get to Meet Immune System...........................................................................5
B Cells and Ab Responses..............................................................................................7
Cells and Cell-Mediated Immunity..................................................................................9
T and B Cell Development and Thymus.........................................................................12
Cytokines, Lymphocyte Surface and Adhesion Molecules...............................................15
How Immune System Deals with Infections...................................................................19
Immunodeficiency (ID).................................................................................................22
Hypersensitivity..........................................................................................................23
Autoimmunity.............................................................................................................25
Immunology in Diagnostic and Clinical Medicine...........................................................28
Factors Influencing Immune Responsiveness......................................................................................32
Overview of Immunity and Immune System
What is the Immune System?
non-specific or innate immune mechanisms 1st line of defence against infectious agents
generally very effective at preventing invasion but if are breached, specific immune system called upon
both immune systems composed of variety of molecules and cells distributed throughout body
interdependent with considerable interaction between them
Non-Specific Immune System Specific Immune System
Repeated infection
resistance not improved resistance improved
Soluble factors Ab’s, complement, acute phase proteins, interferons (IFN and IFN
lysozyme, complement, cytokines
Cells phagocytes, natural killer (NK) cells
lymphocytes, monocytes, APC
Non-Specific Immune System
exterior (especially skin) presents effective barrier to most organisms
importance evident when individual suffers serious burns
most enter via epithelial surfaces (nasopharynx, gut, lungs or GU tract)
variety of physical and biochemical defences protect these areas from most infections
after penetration encounters phagocytic cells of reticulo-endothelial system
macrophages process Ag as well as engulfing them – vital in specific and non-specific immunity
Acute Phase Proteins
acute phase proteins in response to early ‘alarm’ mediators (e.g. IL-1) released by tissue injury
many produced in liver, activate complement, phagocytosis by opsonization and bacterial enzymes
Specific Immune System
8 general properties which characterize immune system:
processing of molecular shape
can recognise diverse range of Ag’s
generates response specific to stimulus
responds to unexpected stimuli
effective discrimination between self and non-self Ag’s
adaptability to provide rapid, appropriate responses
specific immunological memory
regulation by complex 'internal' and 'external' networks
immune system consists of collection of lymphoid organs connected by circulatory and lymphatic system
10 lymphoid organs 20 lymphoid organs
Role mature stem cells into Ag-sensitive T or B lymphocytes
receive mature lymphocytes formed in primary organs
Components
bone marrow (source of stem cells and B lymphocytes)
spleen, lymph nodes, gut-associated lymphoid tissue (GALT – tonsils, adenoids, Peyer’s patches)
10 lymphoid organs 20 lymphoid organs
thymus (source of T lymphocytes)
fetal liver (source of stem cells and B lymphocytes)
blood and lymphatic vessels connect organs to provide comprehensive network throughout body
enables lymphocytes and granulocytes to circulate freely and quickly reach important areas
permits Ag entering body to be brought rapidly into contact with effector mechanisms for disposal
Cells
cells include lymphocytes, macrophages, monocytes and APC (APC)
can be subdivided into number of subpopulations on basis of functions
effector’s responsible for responding to and disposing of Ag’s, regulator’s for control of effector cells
Group Cell Description SurfaceMarkers
Effectors B Ab production CD20
CTL T cell-mediated cytotoxicity CD8
NK/K Natural killer cells (early defence in anti-viral and tumour immunity)
K/Null Ab-dependent cell-mediated cytotoxicity (ADCC) CD16, CD56
Regulators
TH Induction of effector responses
(helper/inducer, recruit non-specific mechanisms. TH1 and TH2 subsets)
CD4
TS Suppression of some effector responses (indistinguishable from those responsible to cytotoxicity)
CD8
How Ag’s get to Meet Immune System
How Foreign Ag’s Meet Immune System
response of immune system to foreign substance depends on nature of substance and route of entry
Route of Entry Response
Skin much foreign matter dealt with at 10 site (local ingestion by macrophages)
Agic fragments are transported in macrophage-like phagocytic cells to local lymph nodes (and spleen), or arrive by themselves at node and are collected by resident scavenger macrophages
in node, Agic fragments passed to dendritic reticular cells (specialized APCs) which process fragments into smaller pieces (epitopes) and present them to Ag-sensitive T and B lymphocytes
Bloodstream filtered out by macrophages in spleen (capable of mounting immune response), liver and lungs
Upper respiratory, GI tract filtered through local lymph nodes and specialized lymphoid organs in gut
Spleen
differentiated into two types of tissue: lymphoid white pulp and erythroid red pulp
white pulp, surrounds small splenic aa. from origins to termini (analogous to cortex of lymph node)
red pulp involved in scavenging old RBCs and serves as reserve site for haematopoiesis
within lymph nodes and spleen, T and B lymphocytes reside in specific areas
Lymph node Spleen
B lymphocytes
follicles of cortical region less well-defined follicular areas of white pulp
T lymphocytes
paracortical areas, medullary cords
peri-arteriolar cuffs
macrophages (especially dendritic reticular macrophages) closely associated with lymphocytes, play vital role in presenting foreign Ag’s to lymphoid cells
Reticulo-Endothelial System
bone marrow-derived myeloid progenitors give rise to cells of mononuclear phagocytic system
two main functions, performed by two different types of cells
‘professional’ phagocytic macrophages remove particulate Ag’s
APCs present Ag’s to specific Ag-sensitive lymphocytes
phagocytic tissue macrophages form network called reticulo-endothelial system (RES)
adherence and ingestion by cells of RES is promoted through opsonisation by complement and Ig
once ingested, degraded by cytoplasmic lysosomal granules (characteristic feature of phagocytes)
both respond to and secrete cytokines
phagocytosis and degradation important method of controlling foreign matter and dead/dying tissues, but process has additional importance as it usually first step in process of lymphocyte activation
Tissue
RES Cell Transport destination
Skin Langerhans cells Regional node
Lungs alveolar macrophages
Spleen or regional nodesBlood blood monocytes, splenic macrophages
Liver Kupffer cells
Gut epithelial M cells Peyer’s patches
Functions of APC
Ag collection, concentration, processing and presentation to lymphocytes
co-stimulation (accessory surface molecules, cytokines)
tolerance induction
Major Histocompatibility Complex (MHC)
studies of grafts between different individuals led to identification of cell surface structures associated with tissue compatibility (Ag’s which caused strong immune responses against grafted tissues)
gene complex responsible called major histocompatibility complex (MHC), located on chr 6
aka human lymphocyte Ag’s (HLA)
Class I and Class II MHC Gene Products
class I and II MHC genes code for surface proteins
class I found on virtually all nucleated cells in body, (A, B, C)
class II restricted to B lymphocytes, macrophages and other specialized APC, (DP, DQ, DR)
class I genes expressed as single glycoprotein (43kD) associated on cell surface with 12kD β2-microglobulin
class II gene products are expressed as heterodimers of α and β chains, encoded by genes of HLA-D locus
both have two other important properties: co-dominant and polymorphic
highly unlikely that two unrelated individuals will have exactly same set of HLA genes
MHC Proteins and Ag Presentation
MHC proteins crucial structures for presenting Ag’s to T lymphocytes
both class I and II MHC have groove in top (peptide-binding groove) into which small pieces of foreign Ag can be fitted
some differences between class I and class II in sort of peptides presented
peptide-binding groove on class I restricted to peptides of 8-10 aa, while class II restricted to ~14 aa
Pathways of Ag Processing
Ag processing within cells differs according to whether Ag’s are taken up by cell or originate from within cell
class I peptides usually derived from infectious process or from breakdown of normal cell products
class II peptides usually result from processing of Ag’s taken up and degraded by APCs
not all fragments resulting from Ag processing will be immunogenic epitopes
only those that can bind to peptide-binding groove can be presented to lymphocytes
different people have different MHC molecules and might present different epitopes to immune system
because class I MHC products expressed on virtually all cells, almost all cells can present Agic fragments derived from metabolic breakdown or from intracellular infectious processes
only B cells and certain specialized Ag-processing cells express class II MHC so only these cells can present Agic fragments from ingested material
B Cells and Ab Responses
Summary
Ab’s
2 heavy and 2 light chain, covalently-bonded structure with globular domains and variable (Ag-binding) and constant (biologically-functional) regions
and light chain and , , , and heavy chain classes
allotypic variation is intraspecies allelic variability
idiotypic variation refers to diversity at binding site (relates to hypervariable regions)
functional properties of Ab’s include:
direct neutralization
agglutination
opsonisation
ADCC
complement activation
Class
Properties Serum Ab
IgM large pentamer, confined to bloodstream, does not cross placenta
produced early in 10 Ab responses - good defence against bacterial spread
efficient agglutinator and complement activator
10%
IgG small monomer, diffuses easily out of blood into extravascular areas, crosses placenta
major class in secondary responses
good complement activator, opsonin and Fc receptor-mediated effector mechanisms
70-75%
IgA predominant Ab class in sero-mucus secretions (dimer)
defence of exterior surfaces
15-20%
IgD highly sensitive to proteolysis
receptor on virgin, Ag-sensitive B lymphocytes
trace
IgE high affinity Fc receptor on mast cells and basophils
involved in symptoms of allergy
elevated levels in some helminthic parasite infections
trace
Complement cascade
classical pathway triggered by Ag-Ab complexes, involves formation of C3 convertase from activation of C1, C2 and C4 components
alternative pathway does not involve Ag-Ab complexes but cell wall components
alternative pathway C3 convertase requires factor B, factor D and C3B
cleavage of C3 into C3a and C3b is central event in complement activation
C3b binds to cell surfaces and serves as focus for activation of late components (C5 to C9) cell lysis
Generation Of Ab Responses
10 Ab responses result from activation of naive, Ag-sensitive B cells, 20 (or anamnestic) responses result from activation of (long-lived) memory B cells
generation of Ab responses occurs in 20 lymphoid organs after Ag-sensitive B cells have bound sufficient Ag through their surface Ig (sIg) receptors and received activation signals from TH
cells
activation of Ag-sensitive B cells results in proliferation and maturation to form population of plasma cells which secrete Ab’s of same Ag-binding specificity as was present on sIg of their precursor B cell, and population of memory B cells which can be restimulated subsequently to produce secondary responses
IgM 1st class of Ab’s produced in 10 response and then class switches to IgG
IgG predominates in 20 responses although small IgM component generally still evident
term affinity refers generally to strength of binding between receptor and its ligand
In Ab response, there will be range of Ab affinities generated and average affinity of Ab population produced will depend on concentration of Ag and immunological history of individual
Immunological Memory
during course of Ab response, new population of small B lymphocytes (memory cells) distinct from Ab-forming plasma cells are generated
histologically, memory B cells appear very similar to original small, Ag-sensitive B cells
role is 'super' Ag-sensitive cells
serve as replacements for their original Ag-sensitive precursors but have lower activation threshold so can be stimulated more easily
can mount more vigorous response than naive B cells so give higher concentrations of Ab’s (usually of different class) that persist for longer periods in serum
Ab Class Switching
IgM 1st class to be synthesized in 10 Ab response but after time replaced by production of IgG
individual activated B cell clones begin by producing IgM but subsequently switch to IgG production
B cell remains true to Ag that originally stimulated it, although some mutation of Ag-binding region fine tuning specificity
IgG synthesis dramatically increased in 20 responses because memory B cells preferentially make IgG
IgM component of 20 response mostly due to activation of new naive Ag-sensitive B cells
Cells and Cell-Mediated Immunity
Natural Killer (NK) Cells
NK cells generally large granular leukocytes comprising 1-5% mononuclear cells in blood
present in spleen and peritoneal exudate, absent from thymus and few in lymph nodes and bone marrow
can be identified by presence of Fcγ receptor (CD16) and CD56 surface marker
do not have to recognize target Ag’s in association with MHC determinant
do not require activation by Ag, although activity by certain cytokines (e.g. IL-2, IFN-γ)
limited repertoire of receptors directed at CHO-containing target structures
recognize targets by variety of mechanisms:
e.g. IgG Fc-γ receptors (CD16) to bind Ab’s bound to target cells and activate NK cell
even target cells resistant to NK cytotoxicity in absence of Ab can be killed by ADCC mechanism
another way NK cells might recognize target cells is through combinations of adhesion molecules such as various of integrin and cell adhesin molecules
very little known about origins or their lineage relationships, but thought to develop in bone marrow
mice with SCID genetic mutation don’t develop T and B cells but have normal NK cells, indicating that NK cell development diverges from B and T lymphocyte development relatively early
Adoptive Transfer
possible to temporarily transfer immunity passively by injecting Ab’s from donor
provides short-term immunity, dependent on half-life of transferred Ab’s in recipient
situations where adoptive transfer of Ab’s does not protect against infection (e.g. intracellular parasites)
transfer of immunity can often be effected by injection of lymphocytes from immune donor
cytotoxic T-cells, rather than B-cell, important in this effect
Cell-Mediated Immunity and Graft Rejection
cell-mediated immunity (CMI) = any response in which Ab’s play subordinate role
most responses involve both Ab and cell-mediated events, each influencing degree and magnitude of other
tissue transplanted from one animal to a genetically-dissimilar animal does not survive long
initially graft tissue begins to grow and be accepted but after days-weeks (depending on type of tissue and amount of genetic dissimilarity) graft begins to die
histologically, lymphocytes infiltrate graft and some appear to attack and kill cells of graft
by using adoptive transfer techniques, found that T-cells most important
if 2nd graft from same donor placed on same recipient at later time, rejected much more rapidly, showing that immune responses capable of developing immunological memory
grafts between genetically-identical pairs not rejected because Ag’s not recognised as foreign
tissue from genetically-identical donor syngeneic, from genetically-unrelated donor allogeneic
immune responses that occur in graft rejection called alloreactive responses
Mixed Lymphocyte Reaction
similar immunological rejection processes occur when blood is transplanted from one individual to another
immune responses occurring during graft rejection can be mimicked by mixing lymphocytes from different individuals in culture and observing reaction over few days by measuring uptake of radioactive nucleotides
test called mixed lymphocyte reaction (MLR) and is still important way to test immunological compatibility
Cells and MHC-Restricted Recognition of Ag’s
T cells and B cells do not respond to exactly same foreign determinants
T cells respond best to Ag’s associated with cell surface
B cells bind soluble Ag’s
proof:
infect mouse from one inbred strain (strain 1) with lymphocytic choriomeningitis virus (LCM virus)
short time later, when cytotoxic T cells specific for virus-infected target cells developed, remove spleen from mouse and study specificity
found that virus-specific TCT could effectively kill infected target cells derived from syngeneic mouse (i.e. strain 1) but would not kill infected target cells derived from allogeneic mouse (i.e. strain 2)
indicates that cytotoxic T cells not only recognizing Ag’s specified by LCM virus but also some normal component of infected target cells
so T cell receptor for Ag more complex than surface immunoglobulin receptor in that it recognizes foreign Ag’s in association with some normal 'self' Ag’s
shown to be MHC
MHC-restricted recognition of Ag general property of T lymphocytes, although different T cells recognize Ag’s associated with different MHC structures
Ag-Recognition Surface Molecules on T-Cells
all T cells have complex of transmembrane proteins (CD3) on surface, known to be required for activation
TH cells also have CD4 molecules and TCT cells CD8
both CD4 and CD8 are intimately associated with CD3
T cells have two other transmembrane polypeptides involved in Ag recognition
called α and β chains, together known as T cell receptor (TCR)
striking similarities between structure of Ig and TCR: both chains have constant and variable domain, hydrophobic membrane-spanning region and short intra-cytoplasmic domain
genes that coding for TCR possess similar arrangement to that found in Ig genes
variable regions undergo rearrangement during T lymphocyte maturation in thymus
Ag Recognition and Roles Of CD4, CD8 & CD3
both CD4 and CD8 T lymphocytes use same genes to synthesize TCR
CD4 helper T lymphocytes: class II MHC-restricted recognition of Ag’s
CD8 cytotoxic T lymphocytes: class I MHC-restriction Ag
CD4 and CD8 bind to non-polymorphic regions of class II and class I respectively
TCT lymphocytes potentially able to recognize Ag’s expressed on any nucleated cell in body
TH lymphocytes have much more limited Agic universe
CD3 (intimately associated with TCR) consists of complex of 5 polypeptide chains
must be involved in activation, as monoclonal Ab’s against CD3 block induction and effector phases
other surface molecules involved in complex process of interaction, but TCR, CD4/CD8, and MHC contribute most to specificity
Clonal Selection and T Cell Activation
20 lymphoid organs and circulating lymphocyte pool contain repertoire of Ag-sensitive T cells, each cell bearing set of TCRαβ receptors through which it can recognize outside world
foreign Ag’s come into contact with these T cells
those that can bind strongly to foreign Agic determinants presented in MHC are selected and activated
as well as requirement for binding to Ag presented by MHC activation requires and interaction between other surface molecules called co-stimulators
without co-stimulator activation does not occur and T cell can become anergized
include B7 expressed on activating APC and CD28 expressed on T cell
for cytotoxic T lymphocyte precursors (CTLP), Ag binding and other surface interactions induces cell to express cytokine-R, in particular IL-2-R (secreted by activated TH cells)
in response to Ag, IL-2 and other cytokines, CTLP can then proliferate and differentiate to form cytotoxic effector cells
cells in cytotoxic clone have same Ag-R and can recognize same foreign Ag presented in MHC
seek out and destroy any cells which bear foreign determinants that they can recognize
during processes of T-cell activation by Ag, memory cells also generated
similar to and have same specificity as precursors but more sensitive and can respond more vigorously
responsible for maintenance of immune state, causes rapid 2nd set rejection in transplant immunology
Cytotoxic Mechanisms Used by CD8 T Cells
do not release effector molecules but require direct physical contact with targets to exert cytotoxic effect
kill targets by three mechanisms
insert complex of molecules called perforin into membrane which assembles into doughnut-shaped holes and compromise integrity of target cell’s membrane
release enzymes which digest target cell membrane
release cytokines that can bind to receptors on target cells and induce apoptosis
T and B Cell Development and Thymus
T Cell Receptor Genes
very similar to Ig genes and are considered part of Ig gene superfamily
divided into arrays of interchangeable V, D and J exons scattered over large tracts of DNA
undergo rearrangement during T cell development in same way as Ig genes during B cell development, so that individual mature T cells end up with ability to produce only one type of receptor
separate gene complexes for α, β and γ chains and each contains V, J and D exons followed by C exons
δ chain unusual in that D, J and C exons are located between V and J exons of α chain gene complex
As result, α and δ chains use same V segments
C gene segments made up of 4 exons which include constant domain segment, short hinge-like region, transmembrane and intracytoplasmic parts
during T cell development in thymus, V, D and J segments are selected and recombined to form complete V-coding domain adjacent to particular C region
Two Types of TCR
most T cells use α and β chains but small subset use γ and δ chains
represent lineage distinct from αβ T cell lineage
found in small numbers in peripheral blood and lymphoid organs (1-10%)
present in larger numbers in intestinal epithelium and represent bulk of dendritic T cells in skin
home to lungs, reproductive tract and spleen
in lymphoid tissue, γδT cells reside in regions distinct from those occupied by αβ T cells; splenic γδ T cells predominate in sinusoids, αβ in follicular areas
majority have CD3 associated with their TCR but lack CD4 and CD8 (although small population of intestinal γδ also have CD8 on their surface)
cannot recognize Ag’s in same way as αβ T cells because do not have CD4 or CD8 molecules
physiological role uncertain, but may have role in control of infectious processes and autoimmunity
relative abundance epithelial surfaces suggests importance as early line of defence
proliferate in response HSPs
T Cell Receptor Diversity
at least 3 highly diverse regions in both α and β chains (correspond to CDRs of Ig)
2 encoded by V gene segments
1 encoded by V and J gene segments (CDR3, in α chain) or V, D and J segments (in β chain)
many fewer V genes employed by TCR than by Ig, other ways are used by TCR to generate diversity - particularly within CDR3 region
include:
N-region diversity documented in all 4 TCR chains but only occurs in 1 Ig chain (heavy chain locus)
large number of TCR J region gene segments (cf. small number in Ig loci)
several Vαs, Vγs and Vδs flexible with respect to position of their 3' joining points (not seen in Ig)
can use both D regions in δ chain and N-region addition occurs at 3 different positions
additionally, translation of D region sequences in all possible reading frames rare in Ig heavy chains but common in TCR β and δ chains, compensating for smaller number of TCR segments
Ig TCR αβ TCR γδ
H κ α β γ δ
Variable (V) segments
~100 ~70 50 57 8 3
Diversity (D) segments
~4 - - 2 0 3
Joining (J) segments 6 5 70 7 3 3
Combinatorial diversity
~106 ~106 ~103
N-region addition V-D
D-J
None V-J V-D
D-J
V-J V-D1
D1-D2
D2-J
Ds read in all frames Rarely - - Often - Often
Somatic mutation yes yes no no no no
Total diversity
by all mechanisms
~1010 ~1010 ~106
concentration of diversity in V-J junction of TCRs may be reflection of known function of TCRs (recognize very diverse small molecules embedded in much less diverse and larger MHC molecules)
γδT cells, in spite of great potential for diversity, show very limited repertoire for V, D and J gene usage
e.g. within given epithelium, γδT cells show little or no diversity
however, certain receptor genes used appear to be specific for location where γδ cell found
B And T Cell Ontogeny and Self-Tolerance
both B and T cell repertoires are designed for maximum recognition versatility
only cells that can recognize Ag through surface receptors activated to generate responses
because there does not have to be exact complementarity between sIg receptors and Ag, cells with range of affinities triggered in response to any particular Ag
high probability that there will always be some cells capable of responding to even most obscure Ag’s
but immune system must be able to discriminate between self and non-self and respond differently
B Cell Ontogeny
lymphoid progenitor cells and early pro-B cells bind to VCAM-1 on bone marrow stromal cells through integrin VLA-4 and other adhesion molecules
promotes binding of surface c-Kit tyrosine kinase to stem-cell factor, inducing proliferation
late pro-B cells require both stem cells factor of stromal cell surface and IL-7 for growth and maturation
first type of cell that can be identified as being committed to B cell lineage is pre-B cell
can synthesize (but not secrete) μ heavy chains (can be observed in cytoplasm)
have undergone DNA rearrangements in heavy but not light chain genes
differentiate further and become fully committed by rearranging either their κ or λ light chain genes so that they acquire ability to make complete immunoglobulins
next, negative selection of self-reactive cells occurs
if immature B cell expresses s-IgM-R that recognizes self Ag in bone marrow it will bind to it
unlike mature B cells, any immature B cells that bind Ag become inactivated
never reach full maturity, and do not appear in Ag-sensitive B cell repertoire of 20
lymphoid organs
immature B cells that don’t recognize self Ag’s permitted to differentiate into fully mature B-cells and express s-IgD and IgM
s-IgD functions as B cell receptor delivering activation signal following Ag recognition, often referred to as triggering receptor
T Cell Ontogeny
T cell development occurs in thymus (bilobed organ overlying heart, each lobe organized into lobules)
in each lobule, bone marrow-derived lymphoid cells arranged in outer cortex of immature proliferating thymocytes and inner medulla of more mature cells
interdigitating bone marrow-derived APCs expressing MHC molecules
both thymic ep cells and interdigitating cells are involved in intrathymic ‘education’ of T lymphocytes
requirements to selection T cell lineage:
effective T cell receptor gene rearrangement
+ve selection for recognition of self MHC
-ve selection to eliminate strongly auto-reactive cells
differentiation of CD4 and CD8 subpopulations
development of αβ and δγ T cell subpopulations
during development, stem cells move from cortex to medulla, becoming progressively more mature
each thymocyte will rearrange either its TCRαβ or TCRδγ genes during sojourn in thymus
cortical thymocytes express CD4 and CD8 accessory molecules (double positive), subsequent maturation leads to these cells becoming ‘single positive’ medullary thymocytes
immature CD4/CD8 cells express only 1/5-1/10 TCR molecules of mature peripheral blood T cells
mature thymocytes develop TCR density ~20-40,000 per cell, similar to peripheral T cells
Positive And Negative Selection In Thymus
of cells expressing TCRαβ are two types of selection that must occur before develop into fully mature T cells
must express TCR which recognizes MHC molecules with low affinity so that they will be able to recognize MHC in association with foreign epitopes with higher affinity (+ve)
must not recognize MHC + self peptide so strongly to be self-reactive in absence of foreign Ag (-ve)
Positive Selection
recognize Ag exclusively in association with self-MHC
not property of all possible TCRαβ combinations
T cells unable to interact with self MHC die in thymus
only T cells with TCRαβ capable of interacting with self-MHC are positively selected for survival
self-MHC molecules responsible reside on thymic epithelial cells of cortex
probably occurs when thymocytes express both CD4 and CD8 accessory molecules
Negative Selection
T cell repertoire arising from random rearrangement of TCRαβ genes would include combinations that would recognize self Ag’s plus self-MHC
strongly self-MHC autoreactive T-cells clonally deleted to maintain self tolerance
for clonal deletion to explain all tolerance every self-Ag in body must manifest itself in thymus
some researchers think idea credible because thymus crossroads for macrophages, other APC and soluble molecules circulating through body
other mechanisms, such as clonal anergy or suppression probably operate as well
Mature Repertoire
as well as selection constraints, repertoire of mature T cells is dynamic and in constant process of flux, influenced by such factors as exposure during life to various microbial Ag’s
analysis of frequency of TCR gene usage shows variation from person to person at any one time
Cytokines, Lymphocyte Surface and Adhesion Molecules
T Cell Subsets And Cytokine Production
TH major source of many cytokines and very influential in modulating immune and inflammatory responses
TH can be divided into different populations on basis of different cytokines produced
TH0 thought to be common precursors
Cytokines produced TH0 TH1 TH2
Cytoxic/Inflammatory (IL-2, IFN-γ, lymphotoxin)
IL-12
TNF, GM-CSF, IL-3
Ab response
(IL-4, 5, 6, 10)
TH1 important in elimination of intracellular infections (e.g. Leishmania)
TH2 responses amplify humoral immune response against extracellular micro-organisms
TH1 and TH2 responses regulated themselves by cytokines produced
IL-4 produced by TH2 cells promotes further TH2 expansion and down-regulates TH1
response while IL-12 promotes TH1 responses and down-regulates TH2 cells
Activated T cells and their ProductsCD8 T cells
Cytotoxins perforin 1, granzymes
Others Fas ligand, IFN-, lymphotoxin
(TNF- and TNF-)
TH1 cells Macrophage-activating cytokines
IFN-, GM-CSF, TNF
Others IL-3, lymphotoxin, IL-2
TH2 cells B cell-activating cytokines CD40 ligand, IL-4, IL-5, IL-6
Others IL-3, GM-CSF, IL-10, TGF-
Cytokines
glycoproteins that act as soluble messenger molecules between cells
initiate many different cellular events including production of further cytokines and other mediators of inflammation, expression of adhesion molecules, cell growth and differentiation
actions of some are inhibitory, playing important role in regulating immune response
number of cytokines termed interleukins (IL) meaning “between white cells”
most cytokines display pleiotropism (diverse actions), redundancy (many cytokines have similar functions), diverse origins, networking and high affinity binding
Class Cytokines Function
Multifunctional
IL-1, TNFIL-6 T and B cell activation, hepatocyte acute phase response, fever induction, IL-1 and TNF mediate fibroblast proliferation, PGE2 and collagenase synthesis, bone resorption
T cell IL-2
(IL-4, IL-6, IL-7)
activation and growth of T helper and T cytotoxic cells
B cell IL-4, IL-5,
IL-6
IL-7
B cell stimulation and growth
B cell differentiation to plasma cells
stimulation of pre-B cells
Haematopoietic
IL-3
G-CSF, M-CSF
GM-CSF
proliferation of haematopoietic cells
granulocyte and macrophage growth /differentiation
eosinophil growth factor
Class Cytokines Function
IL-5,
IL-9
erythrocyte and megakaryocyte growth
Chemotactic IL-8 neutrophil migration and degranulation
Interferons IFNα, IFNβ, IFNγ
anti-viral
enhance HLA Class I & II expression
activate NK cells, macrophages
Growth factors TGFβ, PDGF fibroblast proliferation and matrix synthesis
TGFα, EGF anchorage independent growth
IGF, FGF wound healing
Inhibitory IL-10
TGFβ
CSIF (cytokine synthesis inhibitory factor)
inhibits IL-1 and TNF synthesis
Properties
can be classified on basis of their functions, emphasizing role in regulating immune response
Innate Immune Response important in viral and bacterial infections
e.g. IFN-α & β play vital roles in viral infections, TNF-α, IL-1 & 6 important in bacterial infections
TNF-, IL-1 and IL-6 all inflammatory responses (“pro-inflammatory” cytokines)
Adaptive Immune Response IL-1 (and to lesser extent TNF-) secreted by APC following Ag presentation, and has been termed second messenger for T cell activation
stimulates secretion of another cytokine, IL-2, by TH, which stimulates T cell proliferation
link initial “innate” response with specific “adaptive” immune response driven by Ag
IL-2 originally called T cell GF as its main action is T cell growth and clonal proliferation
produced mainly by TH, has autocrine and paracrine effects
IL-2 also important stimulator of NK cell activity and may help to stimulate B cell growth
IFN-γ
IL-4 performs important function in switching Ab production from IgM to other isotypes, particularly important in allergy where it promotes production of IgE
IL-1,6 important in promoting B cell differentiation are IL-1 and IL-6
Chemotaxis IL-8 representative of large family of chemokines, small (8-10kD) chemotactic glycoproteins
all contain 2 internal disulphide loops, structurally divided into 2 groups depending on whether cysteines are adjacent (C-C) or separated (C-X-C)
IL-8 is C-X-C chemokine, is produced at sites of inflammation promoting chemotaxis of neutrophils
binds to receptors on neutrophils coupled to GTP-binding proteins and have characteristic structure featuring 7 transmembrane domains
important participants in leukocyte trafficking as they activate integrins, promoting firm adhesion of leucocytes to endothelium as well as directing movement of neutrophils
may be thought of as 20 mediators of inflammation as their secretion is stimulated by pro-inflammatory cytokines
C-C chemokines include monocyte chemotactic protein and macrophage inflammatory protein, play important role in allergic inflammation by stimulating basophils to release histamine
Haematopoietic Growth Factors
number of cytokines appear to act primarily to promote growth and differentiation of various lineages of haematopoietic cells
Anti-Inflammatory Cytokines - Promotion Of Repair
TGFβ produced by certain tumours, allows normal cells to grow in soft agar
important immunoregulatory properties, secreted by Ag-activated T cells and macrophages
highly pleiotropic – can or growth of many cell types depending on experimental conditions
important actions on T cell proliferation and maturation of cytotoxic T cells
can synthesis of pro-inflammatory cytokines such and counteract effects of others
promotes wound healing by generation of connective tissue and new blood vessels
IL-10 (aka cytokine synthesis inhibitory factor, CSIF) important in regulating inflammatory response
FGF, PDGF, IGF all important growth factors participating in wound healing
Cell Adhesion Molecules
fundamentally important to cell, determining whether it circulates or moves from blood vessels
granulocytes and monocytes migrate through vessels in response to changes in adhesion molecules expressed by endothelial cells and home to target areas within tissue - do not recirculate
lymphocytes continually patrol body for foreign Ag by recirculating from blood stream, into tissue, through lymph nodes, into lymph and ultimately back to blood stream
also involved in growth and development of tissues, wound healing and tumour invasion
4 major families of cell adhesion molecules which work in co-ordinated way to facilitate movement of leucocytes and their interaction with endothelial cells and ECMFamily Molecule Notes
Sele
cti
ns
mediate processes of tethering and rolling
interactions have rapid association and dissociation constants and so adhesion is short-term and labile
selectins bind to mucin-like ligands, which contain sialylated CHO residues which specifically bind to Ca2+-dependent lectin domain
L-selectin expressed on all circulating leucocytes except for memory lymphocytes
ligands: GlyCAM and CD34 produced by HEV
P-selectin in α-granules of platelets and in pre-formed Weibel-Palade bodies of endothelial cells
ligands: P-selectin glycoprotein ligand (PSLG-1) present on neutrophils
E-selectin induced on vascular endothelial cells by cytokines such as IL-1 and TNF-ligands: sialyl LewisX epitopes on leucocytes
Inte
gri
ns
one of most versatile and diverse families of adhesion molecules, important in cell-cell and cell-ECM adhesion
adhesiveness can be rapidly regulated by chemokines such as IL-8
composed of α and β subunit, subfamilies are classified according to subunit
β1 responsible for cell-ECM adhesion
some recognize tripeptide sequence ‘RGD’ found on ligands (e.g. fibronectin)
interaction between 1 integrin VLA-4 on monocytes, lymphocytes and eosinophils and VCAM-1 on endothelial cells provides important means of leucocyte-endothelium adhesion
2 found on surface of lymphoid and myeloid cells, mediate adhesion of these leucocytes to endothelium
particularly important in neutrophil adhesion as these cells lack 1 integrins
present constitutively on leucocytes and undergo conformational change upon activation to adhesiveness
3 found on platelets
platelet adhesion to fibrinogen, fibronectin, von-Willebrand factor and vitronectin
7 found on lymphocytes and mediates homing of lymphocytes to Peyer’s patches in gut
recognizes ligand on HEV of Peyer's patch called mucosal addressin cell adhesion molecule (MAdCAM-1)
Imm
un
og
lob
ulin
S
up
erf
am
ily M
ole
cu
les
(Ig
SF)
ICAM-1 expressed on inflamed endothelium
binds to LFA-1
ICAM-2 constitutively expressed on endothelial cells
binds to LFA-1 on leucocytes
ICAM-3 expressed on leucocytes
VCAM-1 expressed on activated endothelium
binds VLA-4
MAdCAM expressed by HEV of Peyer’s patches
MAdCAM-1 also contains mucin-like domain which can bind L-selectin and mediate lymphocyte rolling
Cad
heri
ns
Ca2+-dependent adhesion molecules, mediate “homophilic” cell-cell binding
N-cadherin (neural tube)
expressed in embryonic ectoderm and influences separation of neural tube tissue from ectoderm
Leucocytes in Inflammation
leucocytes circulating in bloodstream must be able to slow down and stop within blood vessels near site of inflammation, adhere strongly to endothelium, penetrate into underlying tissue and migrate through ECM
Rolling and Tethering
selectin molecules bind mucin-like CHO ligands
initially (within seconds) P-selectin expressed on surface of endothelial cells, hooks on to PSLG-1 on neutrophils causing them to roll along endothelial surface
L-selectin on leucocytes then interacts with CD34 on endothelial cells
E-selectin and sialyl-Lewis X interaction occurs later as E-selectin only presented 2-8 hours after stimulation with pro-inflammatory cytokines
Triggering
chemokines act as leukocyte chemoattractants and are produced at sites of inflammation
diffuse outward producing concentration gradient down which leucocytes migrate
also produced by endothelial cells under influence of other cytokines (e.g. IL-1 and TNF-α)
platelet activating factor, CD31 and C5a other important chemoattractants
chemoattractants from endothelial cells attach to chemoattractant-R on leucocytes
ligand bound to receptor activates G protein cascade
G proteins transduce signals which activate integrin adhesiveness bringing
Strong Adhesion
leukocyte integrins (e.g. LFA-1) express “activation epitopes” which affinity for ligands >200x
2 integrin/ICAM interactions used by all leucocytes, while T lymphocytes also use VLA-4/VCAM
strong adhesion followed by decay of integrin function allowing cells to be released and extravasate
release phase also associated with shedding of L-selectin from leukocyte surface
migration of leucocytes within tissues associated with β1 integrin interactions as ligands for these adhesion molecules are found within ECM
leucocytes then migrate down chemoattractant concentration gradients to sites of inflammation
Lymphocyte Trafficking
~10% lymphocytes circulating at any time
re-circulating lymphocytes pass from blood through lymphoid system and back to blood
tend to recirculate preferentially to site where they have previously encountered Ag
naive T cells specifically migrate to lymph nodes and memory T cells to non-lymphoid tissue (homing)
specialized cuboidal endothelial cells in HEV express various adhesion molecules (e.g. GlyCAM-1 and CD34) to direct flow of lymphocytes into tissues
molecules which function to direct traffic of T cells through lymph node called addressins
suggested that lymphocyte homing process may also involve sequential steps including selectin-mucin interactions, followed by integrin activation and then coupling with IgSF molecules
interestingly, memory T cells lack L-selectin and therefore do not move through peripheral lymph nodes
long-lived lymphocytes (mostly T and memory cells), most mobile and participate in continual pattern of movement through lymph nodes, spleen, blood and lymphatic system
T-Cell Activation
T cells also use adhesion molecules during adaptive immune response
activation occurs after encounter with Ag-presenting cell when Ag interacts with T cell receptor
adhesion molecules on both cell surfaces are required to stabilize this process
important molecules include 2 integrins, LFA-1, MAC-1 and CD2
corresponding ligands on APC are ICAM-1 and LFA-3
Clinical Applications
current research on cell adhesion molecules extended into clinical field
monoclonal Ab’s to ICAM-1 used in transplantation research to block renal graft rejection
Ab’s to 2 integrins have been used experimentally to prevent cardiac re-perfusion injury by blocking migration of leucocytes to ischaemic tissue
Ab to 1 integrin has been shown to block experimental allergic encephalitis in rats (animal model for MS)
How Immune System Deals with Infections
Process of Infection
often initial focus of infection does not stimulate immune enough to dispose of infectious agent completely
not until agent spread to 20 sites and replicated further that immune systems responds adequately
summary of events: (e.g. bacterial infection occurring at cut in skin)
initial lesion damages tissues and capillaries, provoking local inflammation
chemotactic factors released, attracting phagocytic cells – resulting neutrophil influx cleans up site by ingesting and digesting foreign matter and dead tissue
local mononuclear phagocytes as well as some monocytes also take up foreign matter, break it down into fragments and transport fragments to nearest lymph node through lymphatic vessels
bacteria that have entered lesion may begin multiplying at site
many bacteria will be ingested by local phagocytes, but some may escape and migrate through lymphatic and/or blood systems
other phagocytic cells reside in lymph nodes and spleen which serve to filter such bacteria
Immune Responses to Infectious Agents
complex interactions among microbe, host factors, immunity, and pathogenesis occur during infections and degree and importance of each interaction varies depending on infectious agent
specific immune system can respond to infectious agents in variety of ways, in particular elaboration or inflammatory or inhibitory cytokines, cytotoxic T cell generation, and Ab formation
importance of each depends on nature of infectious agent
Ab’s can be generated against structural Ag’s of infectious agent, or against metabolic products
TCT generation is important in dealing with virus infected cells while of less value with extracellular pathogenic infections such as bacteria
Factor
Micro-organism
Type of micro-organism (e.g.virus, bacterium, parasite)
Dose (i.e. degree of exposure)
Virulence of organism
Route of entry
Host Integrity of non-specific defences
Competence of specific immune system
Genetic capacity to respond normally to specific organism
Evidence of previous exposure (natural or acquired)
Existence of co-infection
Immune Direct neutralization by Ab’s
Opsonization and phagocytosis
Complement-mediated effects
MHC-restricted T cell-mediated cytotoxicity
Inflammatory and immunoregulatory cytokines
Anti-viral cytokines (interferons)
Ab’s In Infection
specific Ab’s in high concentrations at time of infection may act to prevent viruses infecting target tissues
however, if Ab’s not initially present, virus infection will often become well established in target tissues before production has been induced
other immune mechanisms, particularly TCT and TH-mediated effects will be more important
of value in bacterial and parasitic infections if they lead to inactivation or destruction of micro-organisms, but many bacteria have capsules or cell walls that are inherently resistant to complement-mediated damage
in situations where pathogen’s preferred site of infection is phagocytic cell, Ab’s may actually help
may occur in mycobacterial infections where mycobacteria grow inside macrophages and are fairly resistant to killing by Ab-mediated mechanisms
Ab’s at Mucosal Surfaces
adherence to epithelial cells of mucous membranes often essential for viral and bacterial infection
IgA affords protection in external body fluids (i.e. tears, saliva, nose, intestines and lungs)
if infectious agent penetrates IgA barrier, comes up against IgE facet of secretory system
most serum IgE arises from plasma cells in mucosal tissues and in lymph nodes that drain them
although present in low concentration, IgE bound very firmly to Fc receptors of mast cells, and contact with Ag leads to mediator release
Cytotoxic T Cells
because TCT cell activity restricted to recognition of peptides presented by class I MHC, not all Ag’s of pathogens will be accessible as targets of these effector cells
peptides presented by class I MHC arise from cytoplasmic processing of proteins and so only in pathogens that have intracellular cytoplasmic phase will T cell-mediated cytotoxicity play important role
TCT important in most viral infections but will be relatively unimportant in handling extracellular bacteria
recovery from viral infections strongly influenced by TCT activity and interferon rather than Ab’s
Cytokines in Infection
Secondary messengers
important second messengers in cytotoxic T cell and B cell activation
Pro-inflammatory TNFα TNFα mediates defence against bacteria (especially G-), release is triggered by LPS
anti-TNFα results in widespread sepsis and sometimes death
TNFα may enter bloodstream and act as hormone resulting in systemic host response to infection (e.g. fever, acute phase response, cachexia)
IL-1 very similar actions to TNFα, both termed “endogenous pyrogens”
primary source is activated macrophage but also produced by endothelium, ep cells and chondrocytes
second messenger for T cell activation
IL-6 shares many actions with IL-1 and TNF-promotes “acute phase response”, acts upon hepatocytes to stimulate secretion
elevation of fibrinogen is basis of clinical test which gives non-specific indication of degree of inflammation in body; erythrocyte sedimentation rate or ESR
Chemotaxis e.g. IL-8 function to limit infectious processes by aiding chemotaxis and mobilization of effector cells as described
Cytotoxicity IL-2, IFN- NK cell activity and Class I MHC expression NK and cytotoxic T cells lysis
IFN- activates intracellular killing of bacteria by macrophages
Interferon important antiviral proteins
IFN- product of CD4 T cells, IFN– and IFN- transiently induced in most cells of body during viral infection
act on uninfected cells to induce transient antiviral state by inducing of specific enzymes that cleave viral RNA
Helper Cell Subsets in Infection
infectious disease immunology focused for many years on circulating Ab’s or capacity to generate rapid 20 Ab response as most effective means of protective immunity
Ab’s play important role in protection from many viral infections but it is are not only effector mechanism nor are they protective in all infections
not only do TCT responses against virus-infected target cells constitute means of limiting viral infection but many bacterial and parasitic infections appears to depend more on TH than Ab’s
in some cases one class of T cells (e.g. TH1) associated with protection while another class (e.g. TH2) associated with exacerbation
protective immunity must be seen in context of each particular infection as relationship among B cells, TCT, TH and innate (e.g. NK cells) responses which may vary greatly depending on organism associated with infection
unstimulated macrophages do not deliver co-stimulatory signal to T cells recognizing non-bacterial Ag’s and consequently result in T cell anergy
bacteria stimulate macrophages to deliver co-stimulatory signal to T cells recognizing bacterial Ag resulting in proliferation and differentiation to specific T cell effectors
if non-bacterial Ag’s also presented by macrophages induced to express co-stimulatory signal then they too will lead to activation of specific T cells which recognize them
Long-Lasting Immunity
generally speaking, vaccines designed to prevent viral infections do not give same degree of long-lived immunity as natural infection
one of factors contributing to this may be length of time Ag persists in infected or vaccinated individual
Ab-secreting B cells and effector T cells generally have short half-lives (days-weeks)
when Ag persists after infection, memory cells recruited over time and become Ab-secreting cells, thus providing for continual presence of Ab’s or at least allowing rapid production following re-exposure
injected Ag’s trapped in germinal centres of lymphoid tissues and undegraded Ag’s in form of Ag-Ab complexes can persist for long periods on follicular dendritic cells
in this form, Ag is highly immunogenic and can be endocytosed by B cells and presented to T cells, resulting in rapid B cell proliferation with formation of Ab-secreting cells in germinal centres
Host Pathology in Infection
when large numbers of Ab’s produced with high concentrations of Ag’s, Ab’s will bind readily with Ag’s and immune complexes formed will tend to lodge in capillaries of kidney
activation of complement system can result in localized inflammatory reaction causing damage to surrounding tissues and compromising function of organs
when some Ag’s of infectious organism sufficiently similar to some host Ag’s, Ab’s generated against infectious Ag’s may cross-react and damage host tissues
when large numbers of infected cells in vital organ killed rapidly by TCT, organ may be unable to fulfil its functions properly
mechanism important in hepatitis B infections and in AIDS
Immunodeficiency (ID)
Classification
immune system has many components: Ab’s, complement, B and T lymphocytes, cytokines and receptors, adhesion and other accessory molecules, HLA Ag’s, phagocytes etc
malfunction of any may result in state of immunodeficiency
Classification
congenital (due to genetic defect or in utero disease)
acquired (in addition to HIV, acquired ID may be secondary to drug therapy or systemic disease)
primary (inherited / genetic)
secondary (due to some other factor, e.g. HIV)
according to part of immune system affected (humeral, cellular, combined, complement, and phagocytic)
selective IgA deficiency is common (~1/500 people), but other primary ID are rare
Primary ID Syndromes
very heterogenous range of syndromes
molecular basis of many ID is now known, and in future they will be classified by their cause
most due to autosomal or X-linked recessive gene defects
Name Notes
Adenosine Deaminase (ADA) deficiency
build-up toxic byproducts of purine metabolism inside cells, T-cells especially affected
first use of gene therapy, with limited success
Bruton agammaglobulinaemia
mutation in tyrosine kinase enzyme in B lymphocytes
first ID described, X-linked, presents in childhood with recurrent pyogenic infections
Severe Combined Immunodeficiency (“SCID”)
many potential causes, e.g. mutation in γ chain of IL-2-R critical cytokine, also part of receptor for cytokines IL-4, -7, -9, and -15, so has widespread effects
defects in both Ab and cellular immunity
compatible bone marrow transplantation offers only chance of permanent cure
Wiskott Aldrich syndrome defective gene codes for protein that regulates actin cytoskeleton
platelet abnormalities as well as addition to B and T cell problems
Leukocyte Adhesion Deficiency
defect in CD18 adhesion molecule, leukocytes can’t adhere properly, so can’t get to infected and inflamed sites
Hyper IgM Syndrome mutation in CD40 molecule so can’t make class switch
high levels of IgM Ab’s but low IgG and IgA
bare lymphocyte syndrome
transcription of class II MHC genes abnormal, so can’t be expressed on surface
MHC deficiency severely limits ability of T cells to respond to Ag’s
Chronic Granulomatous Disease (CGD)
defective enzymes in NADPH oxidase system needed to produce respiratory burst
defective killing of phagocytosed bacteria
Complement Deficiency Syndromes
may be asymptomatic or unusually prone to infection with certain bacteria
Hereditary angioneurotic oedema
deficiency of C1 inhibitor
Clinical Presentation
usually presents clinically with infection
type of infection is clue to underlying immune defect, but is usually not in itself diagnostic
Organism Immunological Responses
Ab T-cells Other
Extracellular bacteria
IgM, IgG complement, phagocytes
Intracellular bacteria
macrophages
Viruses IgG, IgA complement, IFN
Parasites IgE eosinophils/mast cells
Fungi IgA neutrophils
should suspect ID if patient has recurrent bacterial infections, or infections with unusual organisms
may be family history, many genetically are X-linked so will appear only in boys, most others autosomal recessive
20 ID may be suspected:
in patients taking steroid or cytotoxic regimens for other disorders
with known major disease in other organ systems
with lifestyle risk factors for HIV
should always seek specialist advice before going beyond basic screening investigations
infections should be treated aggressively, and may require prolonged antibiotic therapy
except for Ig replacement therapy for Ab deficiency syndromes, no specific curative therapies for 10 ID
If ID is 20 to medication or disease, if possible underlying problem should be remedied
Immunology Of HIV Infection
well established that HIV infects and depletes CD4 T-cells, molecular pathogenesis still poorly understood
co-factors (e.g. other infectious agents) may be involved
also infects macrophages, Ag-presenting dendrtitic cells, and some haemopoietic stem cells
virus’ gp120 molecule binds to CD4 on lymphocyte and low Mr cytokines receptors (chemokines-R)
some strains have preference for macrophages rather than T cells, and may reflect chemokine-R that predominate on different cell types
certain receptor polymorphisms seem to provide degree of protection, as does strong host chemokine response (competitive inhibition of binding to receptor?)
treatments based on chemokines being developed
infected cells may undergo cell death because of cell fusion/syncytia formation and can act as source of infection in cell to cell transmission
may also have more subtle functional effects on cells it infects, poorly understood
immune destruction results in loss of tumour surveillance, tumour cytotoxicity, and IFN-γ production
autoimmune problems can occur in AIDS, but not usually of clinical significance
result of losing T lymphocytes which normally suppress self-reactive immune responses?
due to excess of Th2 (B cell help) helper T lymphocytes?
vaccination against HIV possibility, and clinical trials with number of vaccines using gp120 are underway
produce successful Ab responses in host, crucial thing is probably to induce cytotoxic T lymphocytes
Reasons for Poor Immune Response
progression associated with preferential loss of TH1 cells
virus mutates very rapidly, and immune system has trouble keeping up
good at “hiding” in dormant integrated state in lymphocytes resting in lymph nodes
current anti-retroviral therapies viral load and prolong survival but cannot eliminate latent virus
Hypersensitivity excessive immune response, so that host is damaged in some way
traditionally been divided into four types of reaction
1: IgE mediated (anaphylactic, or “true” allergy)
2: Ab mediated
3: Immune complex mediated
4: Cell mediated (delayed type hypersensitivity, DTH)
Type I Hypersensitivity : IgE mediated
occurs when divalent allergen cross-links 2 IgE molecules, previously passively bound to high affinity IgE Fc-R
mast cell mediators are released
granule-associated preformed mediators:
histamine, heparin
enzymes: tryptase, b-glucosaminidase
chemotactic and activating factors: eosinophil chemotactic factor (ECF), neutrophil chemotactic factor (NCF) and platelet activating factor (PAF)
newly formed mediators:
lipoxygenase products: SRS and leucotrienes
cyclooxygenase products: prostaglandins, thromboxanes
main effects are vasodilatation, vascular leakiness, pruritis, and smooth muscle contraction
may be localised, effects depend on which part of body is involved:
Organ Symptoms
Respiratory tract
allergic rhinitis (hay fever, perennial rhinitis)
sinusitis (NB ? secondary bacterial infection)
asthma (allergic component VERY common)
Eyes allergic conjunctivitis
Skin urticaria (wheals)
angioedema (deeper skin involvement)
Gut food allergy (diarhoea, abdominal cramps, vomiting)
Multiple organ anaphylaxis
generalised anaphylactic reactions can be fatal, as can severe asthma
patient’s with tendency to make IgE Ab’s to multiple allergens called atopic
runs in families, but basis poorly understood: one gene may be for variant of IgE Fc receptor
bronchial reactions to allergens show immediate and late phase reaction
Type 2 Hypersensitivity: Ab mediated
complement fixation: (eg haemolytic disease of newborn, autoimmune haemolytic anaemia)
receptor-binding: blocking (anti-AChR in myasthenia gravis) or stimulating (anti-TSH receptor, Grave’s)
K/ADCC cells: receptors for Fc portion of Ig molecules, and lyse target cells when cross-linked
can be mediated by neutrophils, macrophages, eosinophils, and possibly other cell types
in vivo importance uncertain
Type 3 Hypersensitivity: Immune complex mediated
binding of Ag and complementary Ag
conformational change in Ig Fc allows binding and activation of complement
direct action of complement split products
recruitment of other inflammatory cells by soluble mediators
systemic: classic example is serum sickness, caused by injection of foreign protein
complexes deposit in skin (rash), joints (arthritis) and kidney (nephritis)
formerly seen with horse Ig for tetanus, problem with non-human monoclonal Ab’s used in therapy
postulated mechanism for vasculitis and renal disease seen in SLE
localised: occurs in tissues
farmer’s lung - extrinsic allergic alveolitis caused by inhaled actinomycete fungi which grow in hay, IgG Ab’s from circulation meet this Ag in alveoli
complement activation and recruitment of inflammatory cells
deposition of immune complexes in blood vessel walls
Type 4 Hypersensitivity: Cell mediated (delayed type, DTH)
T cell mediated, takes 24- 48 hours
classic example: reaction to intradermal injection of purified protein derivative of Tuberculin, to test for cell mediated immunity against Mycobacteria
used to assess immunity (e.g. mumps, candida) as part of investigation of suspected immunodeficiency
also mechanism underlying contact sensitivity (e.g. to metals in jewellery)
initial phase involves uptake, processing, and presentation by dendritic cell in skin
presents Ag to T cells locally and in paracortical zones of nearby lymph nodes
T lymphocyte (mainly TH1) secretes cytokines, macrophages are recruited and activated
up-regulation of adhesion molecules and MHC expression on keratinocytes
Autoimmunity tolerance of “self” is central property of normal immune system
if discrimination broken, immune system may react to self structures and cause autoimmune diseases
Mechanisms of Tolerance
Self-reactive lymphocytes are removed from immune repertoire when they are at immature stage of development
There are several possible mechanisms:
clonal deletion - complete removal of self-reacting cells
dominant mechanism for Ag’s expressed in primary lymphoid organs (thymus and bone marrow)
clonal anergy - self-reacting lymphocytes still exist, but are usually resistant to stimulation
important for Ag’s found only in periphery
immunological ignorance
self-reactive cells present, but do not mount pathological response, because Ag’s sequestered or lacking adequate T cell help
immune system needs to see Ag’s in context of certain “danger” signals before it responds
suppression
self-reacting lymphocytes present and potentially active, but are kept in check by “suppresser cells”
discrete suppressor population not found, now thought to be either TH2 or competing anergic cells
AutoAbs
mechanisms causing autoimmune disease are not fully understood
Natural AutoAbs
loss of self-tolerance does not always lead to autoimmune disease
healthy immune repertoire has some B cells which have potential to produce autoAbs
usually IgM, low titre, and/or low affinity
directed against Ag’s that are not normally accessible in significant amounts (“sequestered” Ag’s)
referred to as “natural” autoAbs
postulated that they have regulatory role, or help dispose of breakdown products
Why don’t they cause disease? amounts or affinity are low
need “help” from corresponding self-reactive T helper lymphocyte to get stronger response going
Ab not pathogenic (many of Ab’s associated with connective tissue diseases don’t cause disease)
patient DOES have autoimmune disease, but this is still sub-clinical
AUTOIMMUNITY IS COMMON, AUTOIMMUNE DISEASE IS RARE
Sequestered Ag’s
tolerance not always established to Ag’s normally hidden from immune system (e.g. lens crystallin)
autoAbs can often be detected following trauma (allows contact of Ag with immune system)
may cause frank autoimmune disease (e.g. sympathetic ophthalmia, damaging good eye after trauma or surgery to other)
Cross Reactions
tolerance can sometimes be by-passed by immunization with closely cross-reacting Ag
e.g. Ab’s against viral RNA or DNA may cross-react with self RNA or DNA, may help explain autoAbs to RNA or DNA in connective tissue disease
infection with certain bacteria (e.g. salmonella, shigella, chlamydia) can trigger reactive arthritis
rheumatic fever
similar cross-reactive theories put forward for infection triggering range of autoimmune diseases
alternative term for this theory of autoimmune disease is “molecular mimicry”
Adjuvant Effects
adjuvants non-specifically enhance immune response
mixed with vaccines to improve efficacy and with Ag’s when experimental animals used to produce antisera
can help produce autoimmune disease when mixed with self or cross-reactive Ag’s
experimental examples:
collagen arthritis produced in rats and mice by immunising with bovine collagen in adjuvant, used as model (albeit not very convincing one) for human rheumatoid arthritis
thyroiditis can be induced in rabbits with thyroglobulin in adjuvant
experimental autoimmune encephalomyelitis produced in mice and rats using myelin basic protein, model for human multiple sclerosis
postulated that infections (both bacterial and viral) may have adjuvant-like effect, in particular:
lipopolysaccharide in G- bacteria is polyclonal B lymphocyte activator
superAgs secreted by certain bacteria are polyclonal T lymphocyte activators
Abnormal MHC Expression
viruses may have analogous adjuvant-like effect:
viral infection leads to release of interferons
IFN-γ causes up-regulation of Class II HLA Ag synthesis
most cells (except for immune and haemopoietic) don’t normally express Class II HLA
may present peptides derived from intracellular autoAgs
immune system isn’t normally exposed to these - intracellular version of sequestered Ag’s
T lymphocytes then respond to HLA+ sequestered-self
CD4+ T cells can now provide “help” for B lymphocytes that previously ignored intracellular Ag
examples of MHC Class II up-regulation include:
islet cells in type I diabetes mellitus
thyroid glandular cells in autoimmune thyroiditis
synovial endothelia and lining cells in rheumatoid arthritis
keratinocytes in psoriasis
unresolved issue is whether class II increase is cause or effect
Regulatory Abnormalities
older theory for autoimmune disease was that regulatory suppressor T lymphocytes became defective, allowing emergence of autoimmune processes previously held in check
not widely believed, may regulate size of some immune responses rather than all-or-nothing tolerance effect
Clinical Features Of Autoimmune Disease
vary widely, depending on organ and exactly what immune response is directed against
examples include:
thyrotoxicosis, caused by Ab’s against TSH receptor, mimic action of TSH and stimulate thyroid gland
pernicious anaemia, autoimmune destruction of gastric parietal cells or Ab’s directed against IF itself
idiopathic thrombocytopenic purpura, due to Ab’s against platelets
Addison’s disease, due to destruction of adrenal cortex
myasthenia gravis, due to autoAbs blocking acetylcholine receptor on NMJ
pemphigus, bullous inflammatory skin disease caused by autoAbs against cadherins
Genetic Predisposition
Factor Notes
Immunoglobulin genes genes for some autoAbs encoded in germline
somatic hypermutation may also be responsible for producing autoAbs
T cell receptor (TCR) some TCR Vß genes are used preferentially by autoreactive T cells
elimination of T cells which use specific Vß genes can prevent or control disease in animal models
with Vß-specific anti-TCR Ab, T cells mediating experimental allergic encephalomyelitis can be eliminated, curing disease
Complement human SLE is associated with deficiencies of complement components
thought to be due to impaired clearance of immune complexes
MHC many autoimmune disease patients have HLA-B8, -DR3 haplotype
rheumatoid arthritis HLA-DR4, ankylosing spondylitis HLA-B27, IDDM aa substitution in β chain of HLA-DQ
area of intensive research
several mechanisms may account for this: peptide binding, molecular mimicry, receptor model
Other genes genome screens have been performed for several autoimmune diseases, and several candidates identified
tend to code for proteins involved in regulating immune response
New Treatment Approaches
cytokine inhibitors: antagonists of TNF-alpha and IL-1 are now in clinical use for rheumatoid arthritis
oral tolerance: works well in some animal models, e.g. multiple sclerosis and arthritis, but so far has had little success in human disease
Immunology in Diagnostic and Clinical Medicine
Summary
make use of exquisite specificity of Ag-binding part of Ab molecule, and detection system attached to constant portion of molecule
can be used to detect either Ag’s, or Ab’s directed against them
ELISA
enzyme-linked immunosorbent assay (ELISA) widely used technique
Step Instructions
1 Ag attached to solid phase (often –ve plastic plate)
best under alkaline conditions (pH 9-10), so Ag’s have net positive charge
2 plate then washed with saline solution (to remove any unattached Ag’s)
wash solution contains weak detergent to help reduce non-specific binding
3 patient’s serum added, diluted in saline solution, incubated with Ag on plate
specific Ab’s attach to Ag, while other Ab’s stay in solution
plate is washed again, removing any unattached Ab
4 addition of “secondary” Ab” directed against Fc portion of patient’s Ab, chemically coupled to enzyme
plate washed again
5 enzyme substrate then added (often horseradish peroxidase (HRP), in presence of H2O2 produces brown colour)
measured by automated spectrophotometer
Results amount of colour proportional to amount of HRP, in turn proportional to how much secondary Ab has bound, in turn proportional to amount of Ab in patient’s serum
Sandwich ELISA Technique
simple variation on basic ELISA principle, and used to detect Ag’s
Ag “sandwiched” between two Ab’s
used to measure wide range of proteins (e.g. polypeptide hormones)
instructions:
coat 1st Ab onto solid phase
incubate patient’s serum, containing Ag, on plate
add Ab directed against same Ag (can coupled directly to enzyme detected by 3rd Ab)
wash plastic plates between successive incubations
colour developing when substrate added proportional to amount of Ag in patient’s serum
Similar TechniquesName Differences Notes
Radio-Immunoassay(RIA)
instead of enzyme, 20 Ab labelled with radio-isotope
most assays are moving towards ELISA instead of RIA because of safety concerns
Micro Particle Enzyme Immunoassay (MPEIA)
solid phase made of numerous microscopic beads coated with Ag
much greater surface area, so much more Ag can be used, making it more sensitive assay
many of serological assays performed in Auckland now performed by MPEIA (eg Hep B, Hep C, HIV 1 & 2)
Radio Allergo-Sorbent Assay(RAST)
20 Ab directed against Fc portion of IgE only
performed to detect IgE Ab’s against specific Ag’s
use Ag that might be causing patient’s allergy (e.g. house dust mite)
most RAST tests are now performed by ELISA or MPEIA, but old terminology still used
allergy usually diagnosed on clinical grounds or with skin testing, and RAST tests are $$$ so only used in special circumstances
Name Differences Notes
Western Blot Ag’s 1st dissociated with detergent, then electrophoresed (SDS-PAGE), separates components according to Mr
transferred to nitrocellulose membrane, incubated with patient’s serum, Ab bind to their respective Ag on membrane
after washing, Ab’s detected using enzyme-coupled 20 Ab
can tell size of Ag
important in diagnosing HIV infection: if patient’s serum tests +ve by MPEIA, Western blot is performed
ideally, Ab’s should bind to p24, p31, gp40, and either gp120 or gp160 of envelope for definite +ve
Immunofluorescence (IF)
fluorochromes (chemicals that emit light when stimulated) can be chemically coupled to Ab
fluorescein (FITC) emits green (520nm) colour, phycoerythrin (PE) emits orange (570nm) colour
Direct IF
can be used to detect Ag’s found in tissue sections, or expressed on outsides of cells
tissue or cells incubated with fluorochrome-coupled Ab
after washing, specimen is examined under fluorescence microscope
areas with Ag show up as bright, coloured regions on dark background (band-pass filtering)
more than one Ag can be detected if Ab’s coupled to difference fluorochromes
Confocal Microscopy
fluorescent images hard to examine at high magnification because of glare from slightly out-of-focus planes
confocal microscope focuses sharp laser beam on fine plane within tissue
photomultiplier tubes scans area, collects emitted light only from same plane, analysed digitally
result is high definition image that looks like very thin cross section of tissue
can image organelles within cells, and examine proteins secreted immediately surrounding cell
Indirect IF
analogous to ELISA technique, often used to detect autoAbs
ANA
anti-nuclear Ab’s (ANA) present in many patients with SLE, detection useful for diagnosis
assay starts with tissue section (or cultured cells) with prominent nuclei
attached to glass microscope slide, treated with chemical fixatives to stop Ag’s degrading and make membrane permeable (allows ANA to access nucleus)
patient’s serum added, and incubated with fixed tissue
after washing, FITC-coupled anti-Ig 20 Ab is added
after washing, anti-Ig will only remain if serum contained anti-nuclear Ab’s
quantitated by performing serial dilutions (1:10, 1:20, 1:40, 1:160, etc) of patient’s serum
result expressed as highest dilution that gave positive result
because some non-specific binding can still occur, ANA below 1:40 regarded as -ve
different nuclear Ag’s (e.g. nucleoli, centromere, DNA) distributed differently within nucleus
ANCA
anti-neutrophil cytoplasmic Ab’s (ANCA) found in patients with vasculitis
assay performed as above, but using neutrophils
different patterns (perinuclear (pANCA) and cytoplasmic (cANCA)) associated with different types
Ag’s involved are enzymes myeloperoxidase and proteinase 3, respectively
Flow Cytometry
cells in suspension incubated with fluorochrome-tagged Ab’s, then washed
labelled cells pass through flow cytometer one by one
laser beam focused on each cell and fluorescence analysed, size and granularity of cell also measured
by using Ab’s against surface Ag’s, composition of cell population can be precisely determined
measurements are quantitative, so that estimate can be made of amount of Ag on particular cell type
possible to simultaneously examine up to 4 different Ag’s on each cell, but usually only 1 or 2 are
e.g. determination of ratio of CD4+ to CD8+ lymphocytes in AIDS patients: lymphocytes incubated with mixture of anti-CD4 (coupled to fluorescein) and anti-CD8 (coupled to phycoerythrin)
also used to examine white blood cells from patients suspected to have leukaemia: different types of leukemic cells have particular combinations of CD Ag’s on their surfaces
able to sort each cell into different receptacles
e.g. peripheral blood lymphocytes could be separated into CD4 and CD8 subpopulations
currently only done in research settings
Immunocytochemistry
used to examine tissue under microscope for presence and distribution of particular Ag
enzyme-coupled Ab used, yielding insoluble coloured product
stays in tissue where Ab bound to Ag, and can be seen down microscope
disadvantages: lower definition but adequate for lower power microscopy
advantages: can be examined with ordinary microscope, colours also last long time
similar technique can be used with transmission electron microscopy (EM), but Ab’s coupled with gold This is
Complement Fixation Tests (CFT)
often used to diagnose recent infections with organisms that are hard to culture
e.g. in diagnosis of recent infection with adenovirus, respiratory syncytial virus, influenza and B, parainfluenza 1- 3, Mycoplasma pneumoniae and Chlamydia psitticae
steps:
patient’s serum incubated with preparation of viral Ag’s
if patient’s serum contains Ab’s against virus these will bind virus to form immune complex
complement then added and immune complexes bind, then fix complement
sheep red blood cells (SRBC) that incubated with anti-SRBC added to mixture
if there complement left (i.e. no anti-viral Ab’s present), SRBC will be lysed
if no complement left (i.e. anti-viral Ab’s present), SRBC will not be lysed
made quantitative by using serial dilutions of serum
many patients will have Ab’s against common viruses because of prior infection, so to diagnose recent infection, need to show 4-fold rise in titre between acute and convalescent phases
Complex Formation
Immunodiffusion
when Ab’s combine with complementary Ag’s, insoluble complex forms and precipitates
can be visualised in several ways
Ab and Ag diffusing towards each other from two small wells cut in agar gel will form visible line
Ag embedded in agar and serum put in well, visible ring will form as Ab slowly diffuses away from well
to assay for Ag, Ab embedded in gel, and serum added to wells
diameter of ring proportional to concentration of Ab
technique known as radial immunodiffusion
used to measure auto-Ab’s against certain of nuclear Ag’s (e.g. ANA SSA and SSB)
Nephelometry
serum mixed with Ag in clear tube
light passing through tube is impeded by complexes, measured by spectrophotometer
light absorption proportional to amount of Ab present
used to quantitate Ab’s against DNA in SLE patients
Agglutination
IgM Ab’s are much more effective at agglutination than IgG
classical application is blood grouping
Ag’s can also be artificially coated onto red blood cells
other particles (e.g. microscopic latex beads coated with Ag’s) can also be used
HLA Tissue Typing
performed to achieve close match between recipient and donor before organ transplant
Lymphocytotoxicity
traditional method uses cytotoxicity assay
peripheral lymphocytes incubated with wide range of Ab’s directed against all main HLA Ag’s
complement added, if lymphocytes have Ag, will be lysed by respective antisera
>100 different antisera are used to determine person’s HLA-A, B, and C Ag’s
anti-HLA antisera are scarce and expensive, so assays scaled down to microlitre proportions
Polymerase Chain Reaction (PCR)
now use PCR to determine HLA types
match PCR primers (“sequence specific primer”, SSP-PCR)
probe PCR products with labelled nucleotides
directly determine DNA sequence of patient’s HLA genes
currently PCR mainly used for class II typing but may eventually replace all cytotoxicity assays
Mixed Lymphocyte Reaction (MLR)
if lymphocytes from 2 patients mixed together, recognise other HLA Ag’s (mainly class II) as “foreign”, and begin to proliferate
in vitro equivalent to early stages of graft rejection
Factors Influencing Immune Responsiveness
Immune System Control Mechanisms
numerous factors that affect nature, magnitude and effectiveness of immune response to Agic challenge
include:
nature of Ag, route of Ag entry and concentration of Ag
presence, concentration and class of specific Ab’s
current immunological state and intercurrent Agic stimuli, Agic history of individual
idiotype/anti-idiotype networks
nature and diversity of Ig and TCR gene families
Ag processing and association with MHC gene products
status of helper T cell involvement and cytokine production
interactions within neuro-immune network
Adaptive and Innate Immunity
diversity imposed by need to recognize all possible self and non-self molecules produces two limitations
cells which recognize self molecules must be rendered ineffective to avoid autoimmunity
lymphocytes of any one specificity will be rare in total repertoire
significant lag phase during which rare lymphocytes undergo expansion before sufficient generated
initial phase characterized by absence of effective adaptive immunity and innate system plays crucial part
main difference between innate and adaptive immunity is system of recognition
innate immunity utilizes limited repertoire that discriminates some common pathogens from self
adaptive immunity distinguishes among infectious agents using receptors that diversify in somatic cells
Ag And Ab Effects
nature of Ag affects sort of immune responses which can be generated against it
foreign Ag’s similar to self Ag’s may not stimulate good response
how Ag processed and nature of MHC presentation will affect epitopes available for recognition
Ab’s already present in individual can either enhance (by opsonisation) or diminish (by leading to rapid Ag removal) immune response
IgG and IgM Ab’s exert inhibitory and enhancing effects, respectively, on B cells
Idiotype/Anti-Idiotype Networks
hypervariable loops on Ig and TCR can be recognized by appropriate Ab’s
many present significant concentrations only during immune responses
can appear to immune system as novel ‘Ag’s’ and so can stimulate and anti-idiotype response
these anti-idiotypes, in turn, behave as Ag’s to stimulate anti-anti-idiotype response
immune system can contain large network of idiotype/anti-idiotype reactions and response to external Ag will be affected by state of idiotypic interactions
evidence that idiotypic networks formed during development and constitute regulatory mechanism that relates self and non-self Ag’s and controls responses against certain important conserved Ag’s
Cytokines as Modulators
focus on immunological autonomy and self-regulation led to discovery of cytokines, which control information exchange within immune and haematopoietic systems
because of powerful influence on immune function, cytokines often called “hormones” of immune system and has been tendency to consider immunological effects to be 10 function
consideration of immune system as essentially autonomous system tended to reinforce belief “external” factors are of less relevance than “internal” factors
recently, become apparent that to appreciate structure and function of immune system within body, necessary to adopt more expanded view of its boundaries and interactions
has come about as result of four general molecular biological observations:
many cytokines have multiple activities within and without of immune system
some cytokines are also produced by cells not of lymphoid or myeloid lineages
increasing numbers of molecules and hormones from outside immune system (particularly from within nervous system) are being found to have direct influences on immune responsiveness
variety of neuropeptides produced by cells of immune system under appropriate conditions
Nervous Effects on Immune System
nervous system can be considered as having two arms with extensive interconnections: ANS (PNS + SNS) and neuroendocrine system centred on hypothalamic-pituitary-adrenal (HPA) axis
HPA Axis and Immune System
limbic system directly regulates neurohormonal and autonomic outflow of CNS
hypothalamus central to this process, so perturbations of hypothalamus affect immune responses
e.g. lesions in ant hypothalamus Ab response, while electrical stimulation Ab response
lesions in hypothalamus and hippocampus also alter NK activity and T cell function
known for many years that corticosteroids have immunosuppressive effects on variety of immune parameters
phagocytosis , macrophages , B and T cells , lymphocyte migratory patterns, cells in thymus
used for immunoproliferative disorders, some autoimmune diseases, and transplant acceptance
number of non-steroidal hormones associated with HPA axis recently shown to influence immune responses
e.g. sex hormones ; insulin, GH, T4
Neuropeptides, Neurological Mediators and Immune Function
over last 5 years large number of neuropeptides discovered and found to affect immune responses
neurological mediators might act directly on immune cells or indirectly by inducing mediator production
receptors for number of these mediators present immune cells, so likely at least some effects direct
Autonomic Nervous System and Immune System
extensive innervation of all lymphoid tissue by NA nerve fibres
terminate predominantly in T cell-rich regions in lymph nodes
NA predominant NT, but A and SER also used
ablation of SNS augments Ab responses
ablation of PNS depresses immune responsiveness
Classical conditioning of immune responses
1975, discovered that immune responsiveness could be influenced by behavioural conditioning
paired sweetened drinking water with injection of cyclophosphamide (IS drug)
found subsequent administration of sweetened water alone, immune responses
since then, classical conditioning of immune responses has been studied extensively
although changes are not large, has been observed for Ab responses, T cell proliferation, T cell mediated cytotoxicity, TH1/TH2 balance, NK activity and allergic responses
display extinction properties characteristic of classical conditioning
Ag-specific conditioned enhancement also demonstrated
conditioned changes have been shown to affect health and/or survival
recent work implicates vagus nerve as integrally involved in psychoimmune conditioning phenomena
conditioning effects probably play potentially important role in placebo phenomena and in most forms of medical and surgical treatment
Immune Effects on Nervous System
changes in electrical activity and NT levels in hypothalamus correlate with time course of response – information must be passing from immune system to brain
potentially 2 ways this could occur and both probably do
responding lymphocytes might secrete neurological mediators
variety of neuroendocrine mediators produced by immune cells under various conditions
cytokines might directly affect neural tissues
cytokines appear to exert effects on CNS and some may act as intrinsic neuromodulators
activation of macrophages produces IL-1 and leads to altered electrical activity and metabolism of NA, SER and DA, also produced by injected IL-1, can be blocked by IL-1 receptor antagonist
does IL-1 acts directly on brain? preoptic nucleus has IL-1-R but as IL-1 is lipophobic it may have difficulty crossing BBB
active transport might carry it across barrier or might cross vascular endothelium
alternatively, IL-1 might stimulate peripheral nerves (demonstrated by recent findings that if vagus nerve cut below diaphragm, stress-induced IL-1-mediated effects )
Effects of cytokines outside immune system
Stress and immune system
difficult to find many measurable aspects of immune system that cannot be altered by some stressor
impact and direction of effects depends on: quality, quantity, duration (e.g. acute: , chronic: sometimes ), temporal relationship, socioenvironmental conditions, various host factors (e.g. species, strain, sex)
stressors can growth of transplanted tumours
effect might be mediated through non-immune mechanisms (e.g. changes in blood flow)
immune effects probably important because NK activity also compromised, and if effect on NK cells pharmacologically blocked, no in tumour growth
many stressors have involved physical ‘insults’, but impact cannot be explained simply in physical terms
e.g. being placed into established territory of another rat, even for brief period of time, severely inhibits production of Ab to Ag administered before intruder introduced
in such situations, adoption of submissive behaviours correlates most closely with Ab production – Ab responses in non-submissive animals relatively unaffected
if animal perceives stressor to be controllable then effects on immune responses are much less
Stress Immunity in Human Studies
some studies conducted into effect of short-term, laboratory stressors but most centred on more ‘naturalistic’ stressful situations
where perception of stress assessed, -ve correlation between perceived stress and immune responses
most significant correlation is with NK cell activity
notion that critical parameter is perception of stress has important implications, and illustrates how we respond psychologically to our environment can affect how we respond physiologically
Immune System Models
classical immunology, through reductionist scientific research, has shown firstly that our immune systems can respond to foreign Ag’s (such as infectious agents) as well as to Ag’s that are normal components of our bodies, and secondly, that these responses are subject to intricate and complex networks of control
psychoneuroimmunology added another dimension to our understanding by revealing important controlling influence on immune responsiveness of what we believe, think and feel
immune system can be considered as extension of nervous system in many ways
called 'molecular sense organ' which gathers information about our molecular environment
immune responses can also be regarded as forms of behaviour essentially no different from other forms of behaviour and potentially amenable to manipulation by psychological behaviour modification techniques
e.g. deliberate intervention at psychological level or at social level affects both immunological measures and disease activity
extensive associations between 'traditional' immunological parameters, elements of nervous system activity, and psychological variables indicate need to consider immune system not just as autonomous defence mechanism but more as integral aspect of self-definition and self-determination of individual
rather than solely protective defence against invasion from potentially hostile environment, immune system could be better viewed as ‘cognitive’ system involved in continual self generation of individual and, in doing so, supporting integrity of body in optimal relationship to its environment