Lecture 03 Immunopathology 1pp Slides

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Medical Microbiology Immunopathology of Infectious Disease!

Allen H. Pensick, Ph. D., Professor of Microbiology Department of Microbiology, St. George’s

, ,

Lecture 3, Fall 2012

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Study Hints• Keep up with reading assignments

• Attendance of Lecture or other Class activities are required.• Text: Murrary

•

• Questions will be taken at lecture but also encourage you toend questions by email to me. [email protected] with aco to cflemin s u.edu

• Study Chapter 11 Murray: Review Immunology Notesand terminology. (Ch. 12 in 6th edition)

•

• Pre Schedule appointments by calling Ms Ann MarieGeorge, or Ms Carolyn Fleming at 444-4357

•

• Sonic Foundry may not have all of the material recorded

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Lecture and Study Objectives

• Explain the contribution role of the immune response in the

pathogenesis of some of the infectious diseases.

• Apply the basic concepts of the immune response as they relate to

to immune mediation of disease.

• List and describe key features of immune disorders.

• List and describe the major classes of hypersensitivity disorders.

•

immunodeficiency diseases and describe the pathogenesis of

associated diseases process.

•immune system.

• Explain the role of antigen or antibody complexes and the role they

. .

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• It is important to understand the basic concepts of

Immunology and the biology of microbial

dynamics that exists between the host and the

microorganism during an infection.

• It is possible for things to go wrong during this

interactive process in which case pathology may

arise either due to failure of the immune system or

that which is mediated by the immune system.

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Overview of Immunology • “ ,

physical events surrounding immune phenomena”! Simplystated, “It is The ability to tell Self Vs non self, all else istechnical detail”. Self Reco nition is an absoluterequirement for the Immune System to be successful.

• Dysfunctional immune systems can lead to disease andDeath!

– genetic aberrations of immune system – infections that destroy the immune system (e.g. HIV)

–

– senescence

– Genetics, Genomics and Immuno-genomics

• Specific Immune system has dual nature, *Humoral and CellMediated System.

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•development of pathology.



Immunopathology and *Infectious Disease

• Immunopathology is a branch of medicine is asubspeciality of Clinical Pathology which consists of

analysis of body fluids for detection of immune

system diseases.

• wo ma or v s ons o pa o ogy – Clinical Pathology

– .

– The role of infectious disease organisms in the

the study of the pathology of an organism , a tissue

or or an s stem or disease with res ect to the

immune system and its responses.6



Immunology and Its Relevance to Medicine.

• Immunopathology is a subdivision of ClinicalPathology that deals with immune responses

that are associated with disease or a pathogenic

process.

– n o ogy, re ers o amage cause o an organ smby its own immune response, as a result of an

infection.

– In its broadest sense, we can view the failure of the

immune system to respond to a disease in an

of disease.

– Recall the immune system is made up of the specific

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and non specific divisions that interact as the immune

system.



What are the defense mechanisms of

e mmune sys em•

called innate immunity.

• Second Line of Defense: Chemical barriers

protective cells and fluids, and in *inflammatory

response also called innate immunity.

– Inflammasone as inflammation promoter and

regulator.

• r ne o e ense: ap ve mmune

response to invaders called Specific Immunity

.



What are Features of Acquired Immune

Response?•

• Adaptive

•

• Has Memory

• Appropriate (respond to the invader at hand).

• -and repertoire of Ag found in the genes of the

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.



Recall the Dual Nature of the

n egra e mmune ys em c ema cFailure in the innate

immunopathology

Invaders must breach

The innate barriers

And be immunogenic

The host must be

Immunocompetent

To Evoke an

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Immune Response response

Chart from Immunology: Benjamini 2nd edition



Immune Response-Cooperative Effector

ec an sms u y e• Complement

– ass ca a way

• IgM &IgG

– – Opsonization

– Alternative Pro erdin Pathwa

– IgM & IgG with Complement

– Lectin Pathway

• Phagocytosis enhanced by opsonins

• Increased aggressive behavior of Cellular Immunity

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Complement System Acitivation (pp. 117-119 Murray) Study Slide p106 6th ed.

IgM, IgG

Mannose Binding Protein binds to

non reduced mannose, fucose

and glucosamine working to

ac va e comp emen roug

convertase

C3a-C5aÆ Inflammation

C3bÆOpsonization

Complement levels In

circulation can be used

as a diagnostic feature

of disease process.

Activated by Bacterial Cell Surfaces, componenst e.g.

Endotoxin, Microbial Polysacharrides, Aggregated IgA

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What goes wrong? Why does the immune system fail to

detect non-self in microbial populations? Microbial

Pathogenesis?(Ch.19 chart 19.5; Ch. 18-p185 in 6th ed.)

• Microbial o ulations also have strate ies!

– Concealment

– Antigenic variations

– Immunosuppression

– Mimicry

– Molecular Mimicry

– Tolerization

– Gaps in host’s immune repertoire

– Up-seting the balance between antibody and

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an responses



What goes wrong and why does the immune system

fail to detect non-self in microbial o ulations

Microbial Pathogenesis? (Ch.19 chart 19.5)• Microbial populations also have a strategies!

– Temporary immunosuppression by someviruses

– – Some microbes interfere with cell signalingbetween immune cells with cytotoxic T-cells,or with host responses

– Some microbes interfere with local expression

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Fig 18.5 p. 187 Mur. 6th Edition

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Figure 19-5 Bacterial mechanisms for escaping phagocytic clearance. Selected examples of bacteria that use the indicated

antiphagocytic mechanisms are given.

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Exotoxins As Super Antigens• -,

or gram-negative bacteria and include cytolytic enzymesand receptor-binding proteins that alter a function or kill thecell.

• Superantigens, a special group of toxins (Figure 18.3p185 6th ed). that activate T cells by binding simultaneouslyto a T-cell receptor and a major histocompatibility complex

c ass mo ecu e on anot er ce w t out requ r ngantigen.

• This nonspecific means of activating T cells can trigger life-rea en ng au o mmune- e responses y s mu a ng e

release of large amounts of interleukins, such as IL-1 andIL-2.

• u uthe activated T cells causing the loss of specific T-cellclones and their immune responses.

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.aureus, staphylococcal enterotoxins, and the erythrogenic

toxin A or C of S. pyogenes.



Immune Disease and Disorders; Study Slide

• Immune Disorders – Hypersensitivity

• Immunodeficiency

• Immunosuppression

– Autoimmune Disease

– Immunodeficiency

– a rogen c or organ c

• Inappropriate response

enetic or ex osure

– – Inappropriate

Response

• Failure to clear the

infectious disease agent

– Failure to Clear in the

Infectious Disease

pers s en n ec ons

.

– Failure to recognize

“self”

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Immunodeficiency: Study Slide

• mmuno e c ency may

result from – genetic deficiencies

• Immunodeficiencynaturally occurs inneonates and pregnant

– starvation

– drug-inducedimmunosuppression

women.

• Deficiencies in specificprotective responses put

(e.g., steroid treatment,cancer chemotherapy

– chemotherapeutic

serious disease becauseof the infectious agents

suppress on o ssuegraft rejection)

– cancer (especially of

by that response (Murry,Table 14-8 6th 12.9 p 143).

• "natural ex eriments“mmune ce s – or disease (e.g., AIDS)

that illustrate theimportance of specificresponses in controlling

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spec c n ec ons



Immunopathology and Infectious Disease

• Refers to damage to host cells by the effector systems of the immune response resulting from microbially-induced

specific and non specific immune responses.

• Immune response can be protective under some conditions,

.

– lack of an immune response (hypo)

– excessive/unlimited/uncontrolledÆ dama e h er

– Inflammasones

• Probably significant contributor and integral component of

observed signs & symptoms for many infections

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Acute Phase Proteins: C-Reactive

Protein• CRP is Acute phase protein produced by liver during

n amma ory response.

• Rise is due to a rise in the plasma concentrationof IL-6, which is produced in macrophages,

- .

• C-reactive protein blood test

– Low risk < 1 mg/L

– High risk> 3 mg/L

• Patients with elevated basal levels of CRP are at anincreased risk for diabetes, hypertension or cardiovascular disease

• Exercise, lose weight, stop smoking, flaxseed,

aspirin, niacin,, statins, clean teeth

• Metabolic Syndrome (Syndrome X)

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Immune Disorders;;Classification: Murray Ch. 14, p152-154

6th edition 12.7 139

Coombs Classification!

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Murrary Murray Ch. 14,p.1536th ed. 12.1 p 139

Fig.l 14-11. Type Iimmediate

Requires the presence of

IgE (reaginic) Ab which

binds to the Fc rece tors

on the mast cells andBecomes a cell surface

receptor for Antigens.

This process can cause

Anaphylactic reactions

which can Life

rea en ng. e.g.reactions to Bee or Wasp

Venom).

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Type II Hypersensitivity

Fig. 14-12 Type II

6th Fig 12.12 p 140

hypersensitivity:

mediatedby antibody and

.

Complement activation

promotes direct cell

damage through the

complement cascade andby the activation

of effector cells.

Exam les are

Goodpasture's

syndrome, the response

to Rh factor in newborns,

an au o mmuneendocrinopathies. ADCC,

Antibody-dependent

cellular c totoxicit ; I ,

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immunoglobulin.



-6th Fig 12-13).

hypersensitivity: immunecomplex deposition.

Immune com lexes can be

trapped in the kidney and

elsewhere in the body, can

activate complement, and

can cause other damagingresponses. Examples are

serum sickness, nephritis

assoc a e w c ron c

hepatitis B infection, and

Arthus reaction.

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Review Key Concept: Primary and

Microbial Invaders6th fig 10.5 p 106

Figure 12-7 Time course of immune responses. The primaryresponse occurs after a lag period. The immunoglobulin (Ig) M

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.response (anamestic response ) reaches a higher titer, lastslonger, and consists predominantly of IgG.



Antigen/Antibody Precipitatation

Rx: ptimal Proportions•

antigen and antibody must be such that each

antibody molecule can find a binding site on the

antigen at which time precipitation occurs• Antigen Excess can occur early in antibody

production making soluble antigen antibody

comlexes.

• nt o y xcess can orm so ua e ant gens.

• Deposits in the tissue can result in immune

comp ex sease;.30



• Nephrotic Syndrome,Renal Biopsy – IF WithAnti-IgG

•

granular. This patterncorresponds to the

deposition.

• It is the immune

stained.

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Fig. 14-14 Type IV

Delayed-type

hypersensitivity (DTH)mediated by CD4 T cells

. n s case,

chemically modified self-

proteins are processed

cells, which release

cytokines (including

- -

γ]) that promote

inflammation. Other

exam les of DTH are the

6th Fig. 12.14 p 141

tuberculin response

(purified protein derivative

test)and reaction to

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:

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metals such as nickel.

APC, TCR, T-cell

receptor.



Fig. 14-15 Contact and

6th Fig. 12. 15 p 143

tuberculin

hypersensitivityresponses. These type

responses are

cell mediated but differ

in the site of cell

symptoms. Contact

hypersensitivity occurs

leads to the formation of

blisters; tuberculin-type

h ersensitivit occursin the dermis and is

characterized by

swelling.

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Fig. 14-14 Type IV

Delayed-type

hypersensitivity (DTH)mediated by CD4 T cells

. n s case,

chemically modified self-

proteins are processed

cells, which release

cytokines (including

- -

γ]) that promote

inflammation. Other

exam les of DTH are thetuberculin response

(purified protein derivative

test)and reaction to

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:


© 2005 Elsevier

metals such as nickel.

APC, TCR, T-cell

receptor.



Delayed Hypersensitivity pp. 154

•

6th fig 12.8 p 141

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that is maximal 48 to 72 hours after injection and is indicative of prior exposure toMycobacterium tuberculosis



Murray Table 14.8 Infections Associated with

Defects in the Immune Res onse

6th

Table 12.9 p 142•

– Induction by physical means (e.g. burns, trauma)

– Granulocyte and monocyte defects in movement,

phagocytosis or killing or decreased numbers of cells(neutropenia)

–

– T-cells (Di George Syndrome; X-Linked IMD)

– - ’ – Combined Immunodeficiency (T and and B Cell)

pathogens.

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Autoimmune Disease

• Persons are Tolerized to

self-antigens whichprevents autoimmune

lack of tolerization to specificantigens. – Autoimmune reactions result

.

• Deregulation of theimmune response may beinitiated by cross-reactivity

rom e presence oautoantibodies, activated T cells,and hypersensitivity reactions.

• People with certain MHC antigens

with microbial antigens(e.g., group Astreptococcal infection,

are at higher risk for autoimmuneresponses (e.g., HLA-B27 [humanleukocyte antigen], juvenilerheumatoid arthritis, ankylosing,

• Polyclonal activation of lymphocytes induced bytumors or infection e. .,

spondylitis).

– Responses are associated withinflammatory TH1-type

res onses.malaria, Epstein-Barr virusinfection)

– Multiple sclerosis, aninflammatory response directedagainst myelin basic protein,

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responses to one or moreviruses, such as Human

herpesvirus 6 or measles.



S stemic lu us er thematosus (SLE)

• chronic inflammatory

– may affect many organsystems skin, joints andinternal organs.

– e sease may e m or severe and life-threatening for most only a mild disease

– African-Americans and Asians

affected.

– Estimated 500,000 Americanhave been diagnosed with the

– 90% have Discoid rash rather the generalized SLE

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Pediatric Autoimmune Neuropsychiatric

Disorders (PANDA)•

• Describes children who have obsessive

com ulsive disorder OCD and/or tic disorders

such as Tourette’s Syndrome.

• Symptoms worsen following strep. Infections

such as “strep throat” and Scarlet Fever.

• Mechanism at present: It is thought to be

similar to that of Rheumatic Fever know as

Syndenham’s Chorea or St. Vitus dance.





Hereditary Complement Deficiences(6th ed. P 143)

• Deficiencies of C1q, C1r, C1s, C4, and C2 areassociated with defects in activation of the classiccomplement pathway. – reater susce tibilit to o enic us- roducin sta h lococcal

and streptococcal infections (Figure 14-16). – These bacteria escape detection by T cells.

– A deficiency of C3 leads to a defect in activation of both theclassic and the alternative pathways, which also results in ahigher incidence of pyogenic infections.

– Defects of the properdin factors impair activation of the

– Deficiencies of C5 through C9 are associated with defectivecell killing with increased susceptibility to disseminated neisserial

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.



Figure 14-16 Consequences of deficiencies

in the complement pathways6th ed Fig 12-16 p 143

. -

of deficiencies in the

complement pathways.

Factor B binds to C3b on

cell surfaces, and the

plasma serine protease D

cleaves and activates

-

alternative pathway.Factors FI and FH limit the

inappropriate activation

of complement. FH binds to

C3b and prevents

activation and is a cofactor

for FI. FI is a serine

6th ed. P 143

protease that cleaves

C3b and C4b. C1 inh,

C1 inhibitor; SLE,

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sys em c upus

erythematosus.



•

Angioedema, also

called Quinke's

disease.• Persons with it are

born lacking C1

esterase inhibitor

• on-p tt ng ema

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Immunosuppression

• Immunosuppressive therapy is important for reducing

excessive inflammatory or immune responses of macrophages and T cells or for preventing the rejectiono ssue ransp an s y ce s. – Anti-inflammatory treatments primarily target the production

and action of TNF, IL12, and IL-1.

–

may be toxic to T cells. Soluble forms of the TNF receptor andantibody to TNF can be used to block the binding of TNF andprevent its action.

– inhibits the action or causes the lysis of T cells.

– Cyclosporin, tacrolimus and rapamycin prevent the activationof T cells. Anti-CD3 and anti-CD25 prevent activation of T cellsto prevent a response.

– Antibody Administration to costimulatory molecules such asB7 or CD40 ligand at the time of transplant can block proper T-cell activation and romote aner rather than res onsiveness.

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Defective PhagocytesMurrary Page 156 (6th p 144 Fig 12-17)

• People with defective phagocytes are more susceptible to bacterial.

14-17 ).

• Chronic Granulomatous Disease in children who have diminishedlevels of cytochrome b and fail to form superoxide anions.

– Defective Oxygen-Dependent Killing. – Children have an impaired ability to oxidize NADPH and destroybacteria through the oxidative pathway. In patients with

• -immature n the bone marrow. – neutrophils from these patients can phagocytose bacteria but have

greatly diminished ability to kill them.

organisms – lack the filtration mechanism of spleen macrophages. Other deficiencies

are shown in See Murray Figure 14-17 . (Review Next Slide)

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Fig. 14-17 Consequences of phagocyte

dysfunction Murrary Page 156

More Susceptible

To Bacterial Dis.

- - -

46

. . ,

phosphate dehydrogenase; Lad, leukocyte adhesion deficiency.


© 2005 Elsevier



Creutzfeld-Jakob-Spongiform Enephalopathy

(Prion Disease) H&E Immune Failure?

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• CBC Complete Blood • Agar Geloun

• ELISA;Enzyme LinkedImmunoassay and the

mmuno us on es

• Radial Immunodiffusion

• Hemagglutination

; nzymeImmunoassay

• Immunodiffusion

Inhibitition (HAI)• Hemagglutination

• Com lement Fixation• Immuno-electrophoresis

• Fluorescence ActivatedCell Sorting (Flow

Test

• Cellulose AcetateElectro horesis

y ome ry• Coombs, Direct and

Indirect

• Rh and other blood factor tests

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Double Dimension Agar Gel

mmuno us on: Murray Chapter 18

• Gel Diffusion used for examination of .

• Clarified agar gel is used as a matrix for combining diffusion withprecipitation. The reactants simply

• Reactants diffuse to each other andppt.l at the equivalence points.

• Line of precipitation

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Documents

Lecture 03 Immunopathology 1pp Slides