lecture+3+immunopathology+note+form

7/27/2019 Lecture+3+Immunopathology+Note+Form

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IMMUNOPATHOLOGYLecture 3

LEARNING OBJECTIVES At the end of these lectures, you should be able to:

1. Be able to explain the contribution role of the immune response in the pathogenesisof some of the infectious diseases.

2. Revise and apply the basic concepts of the immune response and the mechanisms

involved in the immune mediation of disease.

3. List and describe key features of immune disorders.

4. List and describe the major classes of hypersensitivity disorders.

5. Give examples of the major types of hypersensitivity diseases and describe the

pathogenesis of the diseases process.

6. Give examples of diseases that arise from failure of the non specific immunesystem.

7. Explain the role of antigen or antibody excess as it relates to the development of

immune disease.

8. Formation of antigen-antibody complexes and when these processes can cause

tissue damage.

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INTRODUCTIONIt is important to understand the basic concepts of immunology as is applies to the disciplineof Immunology and the biology of microbial populations to understand the complex dynamicsthat exists between the host and the microorganism during an infection. It is possible for thingsto go wrong during this interactive process in which case pathology a disease process due tofailure of the immune system or that is mediated by the immune system may arise. As youmove forward in your studies of pathology and pathophysiology, it will become apparent thatthe facts you learn in Immunology and Medical Microbiology will be applied when trying tounderstand immunopathology.

Immunopathology* is a branch of medicine is a subspecialty of Clinical Pathology whichconsists in analysis of body fluids for detection of immune system diseases. Thus, it deals withthe immune system and its responses (or failure to respond) in the mediation of a diseaseprocess. Clinical pathology is one of the two major divisions of pathology with the other

pathology, being anatomic pathology (surgical pathology). Our focus will be on the role of infectious disease organism in the process of the development of disease. It includes thestudy of the pathology of an organism, a tissue or organ system or disease with respect to theimmune system and its responses. Our discussion will be on general concepts. To keep thingsin context general revision slides will be included. By and large, this is material you havealready had, but now we will use it in an applied fashion.

_________________________________________________ *Source Wikipedia and Medline for further information on immunopathology, Clinical Pathology, andSurgical Pathology.



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Overview of Immunology• “Immunology is a study of all biological, chemical and physical events surroundingimmune phenomena”! Simply stated, “It is the ability to Self Vs non self, all else istechnical detail”. Self Recognition is an absolute requirement for the ImmuneSystem to be successful• Dysfunctional immune systems can lead to disease and Death!

– Genetic aberrations of immune system – Infections that destroy the immune system (e.g. HIV)

– Exposure to chemicals or radiation – Senescence

- Genetics, Genomics and Immuno-genomics (immunomics)

• Specific Immune system has dual nature, *Humoral and Cell Mediated System

• Inappropriate or inadequate immune response can led to the development of pathology

Immunopathology and Infectious Disease

• Immunopathology is a branch of medicine is a subspecialty of ClinicalPathology which consists in analysis of body fluids for detection of immunesystem diseases. Clinical pathology is one of the two major divisions of pathology with the other pathology, being anatomic pathology (surgicalpathology).• Our focus will be on the role of infectious disease organisms in the process of the development of disease and includes the study of the pathology of anorganism , a tissue or organ system or disease with respect to the immunesystem and its responses.

Immunology and Its Relevance to Medicine.• Immunopathology is a subdivision of Clinical Pathology which deals with immuneresponses associated with disease or a pathogenic process.

– In biology, it refers to damage caused to an organism by its own immune

response, as a result of an infection. – In its broadest sense, we can view the failure of the immune system torespond to a disease in an appropriate fashion a factor in a pathologicalprocess of disease. – Recall the immune system is made up of the specific and non specificdivisions that interact as the immune system.

Major Concept: Recall the Features of Acquired Immune Response• Specific

• Adaptive• Discriminates between self and non self

• Has Memory

• Exhibit Self Tolerance• Appropriate (respond to the invader at hand).• Success depends on the immuno-competency and repertoire of Ag found in thegenes of the individual.

It is important to be able to define the features of the acquired or specific immune response. Itis this concept that enables the immune system to function. The non specific defensemechanisms also play an important role, and in many cases infectious diseases aresuccessful because of problems in the first and second level of defense mechanism. The



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worst case scenario is when the immune system can no longer discriminate between self andnon self which gives rise to a whole host of immune mediated disease processes.

Cooperative Effector Mechanisms• Complement

– Classical Pathway• IgM &IgG

– Cell lysis – Opsonization

– Alternative (Properdin) Pathway – IgM & IgG with Complement

• Phagocytosis enhanced by opsonins• Increased aggressive behavior of Cellular Immunity (CMI)

Recall the Dual Nature of the Integrated Immune System Schematic

responseChart from Immunology: Benjamini 2ndeditionFailures

It is important to keep the dynamics of the immune system in mind with trying to understand

immunopathology. The 1,2, and 3rd

lines of defense work together to provide optimumprotection to the host. If any part of the system is dysfunctional, the expected response maynot occur, and in fact may mediate the occurrence of pathology. The schematic above depictsthe interaction of the systems.



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• Viral Infections/Transformation and Destruction• Parasite Infectections, Invasion

Fungal Infections: Toxins or Invasion• Immune response to invasion• Protection from infection

What goes wrong and why does the immune system fail to detect non-self in

microbial populations? (Microbial Pathogenesis) Murray Chapter 18. Study Slide• Microbial populations also have strategies!

– Concealment – Antigenic variations

– Immunosuppression – Mimicry – Molecular Mimicry – Tolerization – Gaps in host’s immune repertoire – Up-setting the balance between antibody and Th1 and Th2 responses• Microbial populations also have strategies!

– Temporary immunosuppression by some viruses

– Some microbial toxins are immunomodulators – Some microbes interfere with cell signaling between immune cells withcytotoxic T-cells, or with host responses – Some microbes interfere with local expression of immune response in thetissue

What happens when the immune system fails to clear the microbe from thesystem?

• Persistent Infections indicate a failure of the immune system! – assures the continuation of the microbial population• Latent Infections

– Can be reactivated

– May become associated with chronic disease states – May be associated with some forms of cancer – Reactivation

– Old Age – Pregnancy – Leukemias

– Iatrogenic Immune suppression – HIV infection

– Nutritional Status

– Exposure to heavy metals

Immune Disease• Immune Disorders

– Hypersensitivity – Autoimmune Disease

– Immunodeficiency – Immunosuppression

– In appropriate Response – Failure to Clear in the Infectious Disease Agent. – Failure to recognize “self”



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Immunodeficiency• Immunodeficiency may result fromgenetic deficiencies – starvation – drug-induced immunosuppression (e.g., steroid treatment, cancer chemotherapy – chemotherapeutic suppression of tissue graft rejection)

– cancer (especially of immune cells) – or disease (e.g., AIDS)

• Immunodeficiency naturally occurs in neonates and pregnant women.• Deficiencies in specific protective responses put a patient at high risk for serious disease because of the infectious agents that would be controlled bythat response (Murray, Table 12-9).• "natural experiments“ that illustrate the importance of specific responses incontrolling specific infections

Immunopathology and Infectious Disease• Refers to damage to host cells by the effectors system of the immuneresponse resulting from microbially-induced specific and non specific immuneresponses.

• Immune response can be protective under some conditions, damaging under others. – Lack of an immune response (hypo) – excessive/unlimited/uncontrolled damage (hypersensitivity)

• Probably significant contributor and integral component of observed signs &symptoms for many infections

Immuno-pathogenesis• Excessive immune and inflammatory responses triggered by the infection can causedisease.• Acute-phase response to cell wall components, e.g. endotoxin, is a protectiveantibacterial response when limited and controlled.

– Systemic and out of control response can cause life-threatening symptomsassociated with sepsis and meningitis (see Figure 18-4).



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– Tissue damage induced by neutrophils, macrophage, and complement at thesite of the infection and granuloma formation induced by CD4 T cells andmacrophages for Mycobacterium tuberculosis can lead to tissue destruction. – M protein of S. pyogenes antigenically mimics heart tissue

• Such that anti-M protein antibodies cross-react with heart muscle tocause damage.

– rheumatic fever. – Immune complexes deposited in the glomeruli of the kidneycause post streptococcal glomerulonephritis.

– Chlamydia, Treponema (syphilis), Borrelia (Lyme disease), and other bacteriathe host immune response is an important cause of disease symptoms inpatients.

Enhancement of infectivi ty: Antibodies specific for the virus enhance its entry intomacrophages by interacting with Fc and/or complement receptors.

• Suggested role in dengue haemorrhagic fever or dengue shock syndrome. 4types of virus with antibodies that cross react.• Problematic when it comes to vaccine development

T-cell mediatedDamage occurs as a result of cytolysis of infected cells or through cytokine release.

May be linked to delayed type-hypersensitivity (CD4+

mediated) response. Associated cell damage is due to release of:

Proteolytic enzymes• Reactive radicals, e.g., peroxide• Cytokines, e.g., TNF-α.Significant contributor to damage associated with chronic HBV infection.

Some syndromes are due to a combination of di fferent mechanisms, e.g., T celland Antibody-mediatedExample: Rheumatic fever

Proceeded by pharyngitis due to certain strains of Group A Streptococci (GAS) – mainly

S. pyogenes (certain M protein serotypes).Suggested mechanisms involve Streptococcal antigens:

• Evoke cross-reactive T-cells then react with heart muscle and valvular connectivetissue.• Evoke cross-reactive antibodies



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Immune Disorders; Classification: Murray Ch. 12, p139-141

Delayed hypersensitivity p154



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Antigen/Antibody Precip itation Rx; Optimal Proportions• For optimal proportions the concentration of antigen and antibody must be such thateach antibody molecule can find a binding site on the antigen at which timeprecipitation occurs• Antigen Excess can occur early in antibody production making soluble antigenantibody complexes.

• Antibody Excess can form soluble antigens.

Deposits in the tissue can result in immune complex disease; Antibody-mediated

Immune complex diseases: Excessive microbial antigen circulates as complex withantibody.

o Not cleared by RES

o Deposited in tissues, capillaries, glomerular basement membrane, etc.

• Complement activation and inflammation.



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Exotoxins as Super Antigens• Exotoxins , proteins that can be produced by gram-positive or gram-negativebacteria and include cytolytic enzymes and receptor-binding proteins that alter afunction or kill the cell.• Superantigens, a special group of toxins (Figure 18-3) that activates T cells by

binding simultaneously to a T-cell receptor and a major histocompatibility complexclass II (MHC II) molecule on another cell without requiring antigen.• This nonspecific means of activating T cells can trigger life-threatening autoimmune-like responses by stimulating the release of large amounts of interleukins, such as IL-1/IL-2.• Super antigen stimulation of T cells can also lead to death of the activated T cellscausing the loss of specific T-cell clones and their immune responses.• Superantigens include the toxic shock syndrome toxin of S. aureus, staphylococcalenterotoxins, and the erythrogenic toxin A or C of S. pyogenes.



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Murray Table 12.9 Infections Associated with Defects in the Immune Response• Defects caused by pathogenic microorganisms

• Induction by physical means (e.g. burns, trauma)• Granulocyte and monocyte defects in movement, phagocytosis or killing or decreased numbers of cells (neutropenia)• Individual components of complement system

• T-cells (Di Georges Syndrome)• B-cells (Bruton’s Syndrome)• Combined Immunodeficcyien• T and B-cell pathogens.

Autoimmune Disease• Persons are Tolerized to self-antigens which prevent autoimmune disease.• Deregulation of the immune response may be initiated by cross-reactivity withmicrobial antigens (e.g., group A streptococcal infection, rheumatic fever),• Polyclonal activation of lymphocytes induced by tumors or infection (e.g., malaria,Epstein-Barr virus infection)• Genetic predisposition caused by lack of tolerization to specific antigens.

• Autoimmune reactions result from the presence of autoantibodies, activated T cells,and hypersensitivity reactions.• People with certain MHC antigens are at higher risk for autoimmune responses (e.g.,HLA-B27 [human leukocyte antigen], juvenile rheumatoid arthritis, ankylosingspondylitis).• Responses are associated with inflammatory TH1-type responses.• Multiple sclerosis, an inflammatory response directed against myelin basic protein,may be triggered by immune responses to one or more viruses, such as Humanherpesvirus 6 or measles.

Multisystemic Autoimmune Diseases• Systemic lupus erythematosus (SLE)

• Progressive systemic sclerosis (a.k.a. scleroderma)• Rheumatoid arthritis• Sjogren's syndrome• Mixed connective tissue disease

Hereditary Complement Deficiences• Deficiencies of C1q, C1r, C1s, C4, and C2 are associated with defects in activationof the classic complement pathway.• greater susceptibility to pyogenic (pus-producing) staphylococcal and streptococcalinfections (Figure 12-16).• These bacteria escape detection by γδ T cells.• A deficiency of C3 leads to a defect in activation of both the classic and the

alternative pathways, which also results in a higher incidence of pyogenic infections.• Defects of the properdin factors impair activation of the alternative pathwaypredisposes to pyogenic infections• Deficiencies of C5 through C9 are associated with defective cell killing withincreased susceptibility to disseminated neisserial infections.

Defective Phagocytes, Murray Page 143• People with defective phagocytes are more susceptible to bacterial infections but notto viral or protozoa infections (See Murray Fig. 12-17).



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• chronic granulomatous disease in children who have diminished levels of cytochrome b and fail to form superoxide anions.

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

• Chédiak-Higashi syndrome, Fusion of the neutrophil granules in immature n thebone marrow.

– neutrophils from these patients can phagocytose bacteria but have greatlydiminished ability to kill them.

• Asplenic individuals are at risk for infection with encapsulated organisms – lack the filtration mechanism of spleen macrophages. Other deficiencies areshown in See Murray Figure 12-17.

Clincal Immunology: List of Tests• CBC Complete Blood Count• ELISA;Enzyme Linked Immunoassay and the EIA; Enzyme Immunoassay• Immunodiffusion• Immuno-electrophoresis• Fluorescence Activated Cell Sorting (Flow Cytometry)• Coombs, Direct and Indirect• Agar Gel Immunodiffusion Test• Radial Immunodiffusion• Hemagglutination Inhibitition (HAI)• Hemagglutination• Complement Fixation Test• Cellulose Acetate Electrophoresis• Rh and other blood factor tests• PCR

Use of the Adaptive Immune Response to Diagnoses Disease• Determining the homogeneity of antigen-antibody systems• Diagnosing specific autoimmune disorders

• Following the purification of an antigenic mixture

• Elucidating the reactions among serologically related antigens• Determine presence of Microbial Antigens

• Evaluate the serum profle to assist in diagnosis and management.• Determine the immune status of an individual.

– Titers• History of infections can be found in the immune system.

Key Elements of Clinical Laboratory Immunology• Always know the principle of the test, the role of the reactants, and what serves asthe indicator system.• The Parameters of Time, Temperature, pH, ionic strength, and purity of supportingmedia always must be considered.• Know what constitutes a +tive and –tive Test.

• Always have positive and negative controls.• Zeta potential must also be considered when setting up immune reactions.



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