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Disorders of Disorders of ImmunityImmunity
Dr.CSBR.Prasad, Dr.CSBR.Prasad, M.D.M.D.
Immune SystemImmune System AntigenAntigen
Protein substance that stimulates Protein substance that stimulates Antibody productionAntibody production
HaptenHapten – non-protein substance, – non-protein substance, Small mol.wt.Small mol.wt.
AntibodyAntibody Protein substance produced as a Protein substance produced as a
result of antigen stimulationresult of antigen stimulation Circulating Ab are immunoglobulinsCirculating Ab are immunoglobulins
Can you name Can you name one carbohydrate one carbohydrate
antigen?antigen?Blood group Blood group
antigens (ABO sys)antigens (ABO sys)
Immune SystemImmune System Non- Specific Immunity (Innate Non- Specific Immunity (Innate
immunity)immunity)--first line of defence without antigenic first line of defence without antigenic specificityspecificity Humoral – Complement systemHumoral – Complement system Cellular – Neutrophils, MØ, NK cellsCellular – Neutrophils, MØ, NK cells
Specific Immunity (Adaptive immunity)Specific Immunity (Adaptive immunity) Humoral .I - Antibody produced by B cellsHumoral .I - Antibody produced by B cells Cell mediated .I – T cells - produce Cell mediated .I – T cells - produce
Sensitized cellsSensitized cells
Immune SystemImmune System LymphocytesLymphocytes
T lymphocytesT lymphocytes B lymphocytesB lymphocytes
MacrophagesMacrophages Natural killer cells (NK cell)Natural killer cells (NK cell) Dendritic cellsDendritic cells CytokinesCytokines Complement systemComplement system
Immune SystemImmune SystemLymphocytesLymphocytes T lymphocytesT lymphocytes
60-70% peripheral lymphocytes60-70% peripheral lymphocytes Paracortical areas of lymph nodeParacortical areas of lymph node Perifollicular sheaths of spleenPerifollicular sheaths of spleen
T cell Receptor (TCR) – T cell Receptor (TCR) – recognizes specific cell bound recognizes specific cell bound antigenantigen
T cell Receptor (TCR)T cell Receptor (TCR) 95% of TCR is a disulfide linked 95% of TCR is a disulfide linked
heterodimer consisting of alpha heterodimer consisting of alpha and beta polypeptide chainand beta polypeptide chain
Gamma and delta polypeptide Gamma and delta polypeptide chains seen at epithelial surfaces chains seen at epithelial surfaces eg. Respiratory / GIT mucosaeg. Respiratory / GIT mucosa
CD3 proteins are involved in CD3 proteins are involved in transduction of signals into the T transduction of signals into the T cells after it has bound to antigencells after it has bound to antigen
The T-cell receptor (TCR) complex. A, Schematic illustration of TCRα and TCRβ chains linked to
the CD3 complex.
The T-cell receptor (TCR) complex.The T-cell receptor (TCR) complex:B, Recognition of MHC-associated peptide displayed on an antigen-presenting cell (top) by the TCR. Note that the TCR-associated ζ chains and CD3 complex deliver signals (signal 1) upon antigen recognition, and CD28 delivers signals (signal 2) upon recognition of costimulators (B7 molecules).
T - lymphocytesT - lymphocytes Expresses non polymorphous Expresses non polymorphous
function associated molecules – function associated molecules – CD4, CD8 and accessory molecules CD4, CD8 and accessory molecules – CD2,CD9, CD28 and CD40 ligand– CD2,CD9, CD28 and CD40 ligand
CD4 is expressed on 60% of T cells CD4 is expressed on 60% of T cells (Helper T cell)(Helper T cell)
CD8 is expressed on 30% of T cells CD8 is expressed on 30% of T cells (cytotoxic T cell)(cytotoxic T cell)
Markers for B & T cellsMarkers for B & T cells T cell markers are unidigits (Eg: T cell markers are unidigits (Eg:
CD3)CD3) B cell markers are double digits B cell markers are double digits
(Eg: CD20)(Eg: CD20)
T - lymphocytesT - lymphocytes CD4 binds to Class II MHC CD4 binds to Class II MHC
molecule expressed on APCmolecule expressed on APC CD8 binds to Class I MHC CD8 binds to Class I MHC
moleculemolecule CD4+ T cell CD4+ T cell - Master regulator - Master regulator
Influences the function of other T Influences the function of other T cells, B cells, macrophages & NK cells, B cells, macrophages & NK cellscells
The T-cell receptor (TCR) complex.The T-cell receptor (TCR) complex:B, Recognition of MHC-associated peptide displayed on an antigen-presenting cell (top) by the TCR. Note that the TCR-associated ζ chains and CD3 complex deliver signals (signal 1) upon antigen recognition, and CD28 delivers signals (signal 2) upon recognition of costimulators (B7 molecules).
T - lymphocytesT - lymphocytes T Helper- 1 (TH1) subsetT Helper- 1 (TH1) subset
Secretes IL-2 and gamma IFNSecretes IL-2 and gamma IFN Involved in delayed hypersensitivityInvolved in delayed hypersensitivity Macrophage activation and synthesis of Macrophage activation and synthesis of
IgG antibodyIgG antibody T Helper- 2 (TH2) subsetT Helper- 2 (TH2) subset
Secretes IL4 and IL5Secretes IL4 and IL5 Involved in the synthesis of IgE antibodyInvolved in the synthesis of IgE antibody
CD8 T lymphocytes CD8 T lymphocytes secretes IL-2 and gamma IFNsecretes IL-2 and gamma IFN Act as cytotoxic cellsAct as cytotoxic cells
B - lymphocytesB - lymphocytes 10-20 % of circulating lymphocytes10-20 % of circulating lymphocytes Present in BM, germinal centre of Present in BM, germinal centre of
lymphnode and white pulp of spleenlymphnode and white pulp of spleen Activation of B- lymphocytes – Activation of B- lymphocytes –
plasma cells – secretes Ig (humoral plasma cells – secretes Ig (humoral Immunity)Immunity)
IgM present on all B cells form the IgM present on all B cells form the antigen binding component of B antigen binding component of B cell receptorcell receptor
MacrophagesMacrophages Part of Mononuclear phagocytic Part of Mononuclear phagocytic
systemsystem Process and present antigen to Process and present antigen to
immunocompetent T cellsimmunocompetent T cells Important for delayed hypersensitivity Important for delayed hypersensitivity
reaction. Gamma IFN secreted by T reaction. Gamma IFN secreted by T Helper-1 (TH1) subset enhances Helper-1 (TH1) subset enhances microcidal properties of macrophagemicrocidal properties of macrophage
Phagocyte the microbes that are Phagocyte the microbes that are opsonized by IgG or C3bopsonized by IgG or C3b
Dendritic CellsDendritic Cells Interdigitating dendritic cellsInterdigitating dendritic cells
Present in lymphoid cells, interstitium of Present in lymphoid cells, interstitium of heart and lungheart and lung
Epidermis – Langerhans cellEpidermis – Langerhans cell Expresses MHC class II molecule and act as Expresses MHC class II molecule and act as
APC for T cells APC for T cells Follicular dendritic cellsFollicular dendritic cells
Germinal centre of lymphoid follicle in Germinal centre of lymphoid follicle in spleen and lymphnodespleen and lymphnode
Bear Fc receptor for IgG and hence can Bear Fc receptor for IgG and hence can trap antigen bound to antibodytrap antigen bound to antibody
The morphology and functions of dendritic cells (DC). A, The morphology of cultured dendritic cells.
B, The location of dendritic cells (Langerhans cells) in the epidermis.
C, The role of dendritic cells in capturing microbial antigens from epithelia and transporting them to regional lymph nodes.
Natural Killer (NK) cellNatural Killer (NK) cell 10-15% of peripheral blood lymphocyte10-15% of peripheral blood lymphocyte Larger than small lymphocyte and Larger than small lymphocyte and
contain azurophilic granulescontain azurophilic granules Large granular lymphocyteLarge granular lymphocyte First line of defence against tumour First line of defence against tumour
cells, viral infected cellscells, viral infected cells CD16 and CD56 positiveCD16 and CD56 positive Secretes gamma InterferonSecretes gamma Interferon Antibody Dependent Cell mediated Antibody Dependent Cell mediated
Cytotoxicity (ADCC)Cytotoxicity (ADCC)
CytokinesCytokines Messenger molecule of immune Messenger molecule of immune
systemsystem Short acting soluble mediators, Short acting soluble mediators,
involved in the induction and involved in the induction and regulation of immune responseregulation of immune response
CytokinesCytokinesFive groupsFive groups1. 1. Mediate Mediate naturalnatural immunity immunity
IL-1, IL-6, TNF- alpha IL-1, IL-6, TNF- alpha 2. 2. Regulate Regulate lymphocytelymphocyte growth, activation and growth, activation and
differentiationdifferentiation IL-2 & IL-4 – favours lymphocyte growth and Diff.IL-2 & IL-4 – favours lymphocyte growth and Diff. IL-10 & TGF-beta – downregulate immune responseIL-10 & TGF-beta – downregulate immune response
3. 3. Activation of Activation of inflammatory cellsinflammatory cells Gamma interferon, TNF alpha, lymphotoxin (TNF- beta), Gamma interferon, TNF alpha, lymphotoxin (TNF- beta),
MIFMIF4. 4. ChemokinesChemokines – – leukocyte movementleukocyte movement5. 5. Stimulation of Stimulation of hematopoiesishematopoiesis
GM-CSF & G-CSF act on committed progenitor cellsGM-CSF & G-CSF act on committed progenitor cells
CytokinesCytokines Produced by different cell typesProduced by different cell types
IL-1, TNF - alphaIL-1, TNF - alpha Act on many cell typesAct on many cell types
IL-2 act on T cell, B cell and NK cellIL-2 act on T cell, B cell and NK cell Act in 3 waysAct in 3 ways
Autocrine effect – IL-2Autocrine effect – IL-2 Paracrine effect - IL- 7 BM stromal Paracrine effect - IL- 7 BM stromal
cellscells Endocrine effect - IL-1, TNF – alpha Endocrine effect - IL-1, TNF – alpha
(acute phase reactant)(acute phase reactant)
CytokinesCytokines Cytokines mediate their effect by Cytokines mediate their effect by
binding to specific high affinity binding to specific high affinity receptorsreceptors
Useful in therapyUseful in therapy Control the harmful effect of Control the harmful effect of
inflammation/ tissue damaging inflammation/ tissue damaging immune responseimmune response
Enhances immunity against Enhances immunity against cancer/microbial infectionscancer/microbial infections
Histo-Histo-compatibility compatibility
Antigens - Antigens - HLAHLAChromosome # 6Identity of SELF
Histo-compatibility Histo-compatibility AntigenAntigen
Antigens that evoke rejection of Antigens that evoke rejection of transplanted organstransplanted organs
Principal function is to bind peptide Principal function is to bind peptide fragments of foreign protein for fragments of foreign protein for presentation to appropriate antigen presentation to appropriate antigen specific T cellsspecific T cells
MHC antigens – Human Leukocytic MHC antigens – Human Leukocytic Antigen (HLA)Antigen (HLA)
MHC antigens and corresponding MHC antigens and corresponding genes are complex in structuregenes are complex in structure
Histo-compatibility Histo-compatibility AntigenAntigen
Base on structure, distribution and Base on structure, distribution and function of MHC gene productsfunction of MHC gene products
Class I MHC antigensClass I MHC antigens have loci as have loci as HLA- A, HLA – B and HLA – CHLA- A, HLA – B and HLA – C
Class II MHC antigensClass II MHC antigens have single have single locus HLA – D . It has 3 subregions – locus HLA – D . It has 3 subregions – HLA- DP, HLA-DQ and HLA- DRHLA- DP, HLA-DQ and HLA- DR
Class III genesClass III genes - complement - complement
Class I MHC antigensClass I MHC antigens Expressed on all nucleated cells & Expressed on all nucleated cells &
plateletplatelet It binds to peptides that are It binds to peptides that are
derived from proteins such as viral derived from proteins such as viral antigensantigens
Cells process the antigen and Cells process the antigen and transported to cell surface for transported to cell surface for presentation to CD8 cytotoxic T presentation to CD8 cytotoxic T lymphocyteslymphocytes
Figure 6-10 Antigen processing and recognition. The sequence of events in the processing of a cytoplasmic protein antigen and its display by class I MHC molecules are shown at the top. The recognition of this MHC-displayed peptide by a CD8+ T cell is shown at the bottom.
Class II MHC antigensClass II MHC antigens Present only on APC – Macrophages, Present only on APC – Macrophages,
Dendritic cells & B cellsDendritic cells & B cells It binds to exogenous antigens It binds to exogenous antigens
(microbes, soluble proteins) that are (microbes, soluble proteins) that are first internalised and processed in first internalised and processed in endosomes / lysosomesendosomes / lysosomes
Peptide - MHC complex is Peptide - MHC complex is transported to the cell surface, where transported to the cell surface, where it is recognized by CD4 helper T cellsit is recognized by CD4 helper T cells
The T-cell receptor (TCR) complex.The T-cell receptor (TCR) complex:B, Recognition of MHC-associated peptide displayed on an antigen-presenting cell (top) by the TCR. Note that the TCR-associated ζ chains and CD3 complex deliver signals (signal 1) upon antigen recognition, and CD28 delivers signals (signal 2) upon recognition of costimulators (B7 molecules).
HLA & Disease HLA & Disease associationassociation
InflammatoryInflammatory Myesthenia gravis – HLA B8Myesthenia gravis – HLA B8 Ankylosing spondylitis- HLA B27Ankylosing spondylitis- HLA B27 Polygonococcal arthritis – HLA B27Polygonococcal arthritis – HLA B27 Salmonella arthritis – HLA B27Salmonella arthritis – HLA B27 Rheumatoid arthritis – HLA DR4Rheumatoid arthritis – HLA DR4 Chronic active hepatitis – HLA DR3Chronic active hepatitis – HLA DR3 Grave’s disease – HLA DR3Grave’s disease – HLA DR3
Inherited errors of metabolismInherited errors of metabolism 21 hydroxylase deficiency – HLA BW47 21 hydroxylase deficiency – HLA BW47
AutoimmunityAutoimmunity Insulin dependent diabetis – HLA DR4 Insulin dependent diabetis – HLA DR4
&DR3&DR3
OverviewOverview HI --- Ab synthesisHI --- Ab synthesis CMI --- Sensitized cellsCMI --- Sensitized cells TH1 is associated with IgG elaborationTH1 is associated with IgG elaboration TH2 is associated with IgE elaborationTH2 is associated with IgE elaboration NK cells are non-specific in their actionNK cells are non-specific in their action HLA-B27, HLA-DR3 & 4 are more HLA-B27, HLA-DR3 & 4 are more
commonly associated with diseasescommonly associated with diseases CytokinesCytokines
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