Inflammation and Diseases of Immunity and Autoimmune diseases- Lecture Notes PDF

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Summary

Inflammation and Diseases of Immunity Immunity  The ability to resist the harmful effects of microorganisms and other foreign substances o Adaptive immunity exhibits specificity and memory o Innate immunity does not show specificity or memory Innate Immunity  Responds quickly and consists of: o ...

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Inflammation and Diseases of Immunity  Immunity  The ability to resist the harmful effects of microorganisms and other foreign substances o Adaptive immunity exhibits specificity and memory o Innate immunity does not show specificity or memory  Innate Immunity  Responds quickly and consists of: o Mechanical mechanisms  Skin and mucosae prevent entry of microorganisms  Tears, saliva, and mucus remove them o Chemical mediators and Blood proteins (Complement) o Cells (Macrophages, Neutrophils, NK cells) o Inflammatory Response  Complement o

Each complement pathway involves a cascade in which complement proteins are activated in an orderly sequence. The end result is cell lysis, phagocytosis, and inflammation

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Refers to a group of 20 or so proteins that circulate in the blood in an inactive form

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Provides a major mechanism for destroying foreign substances in the body

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Amplifies all aspects of the inflammatory response

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Kills bacteria and certain other cell types (our cells are immune to complement)

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Can be activated by either the classical or the alternative pathway 

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Classical pathway is part of adaptive immunity 

Depends on the binding of antibodies to invading organisms

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Subsequent binding of C1 to the antigen-antibody complexes (complement fixation)

Alternative pathway is part of innate immunity 

Triggered by interaction among factors B, D, and P, and polysaccharide molecules present on microorganisms

 Inflammatory Response o

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Can be initiated in many ways 

Chemical mediators cause vasodilation and increase vascular permeability, which allows the entry of other chemical mediators

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Chemical mediators attract phagocytes

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The amount of chemical mediators and phagocytes increases until the cause of the inflammation is destroyed. Then the tissue undergoes repair

Local inflammation produces the symptoms of 

Redness

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Heat

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Swelling

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Pain

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Loss of function

Symptoms of systemic inflammation include 

An increase in neutrophil numbers

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Fever

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Shock

Mediators of inflammation:  Histamines  Kinins  Prostaglandins  Leukotrienes  Others

 TERMINATION OF THE ACUTE INFLAMMATORY RESPONSE 

The mediators of inflammation are produced in rapid bursts, only as long as the stimulus persists, have short half-lives, and are degraded after their release

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Neutrophils also have short half-lives in tissues

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Inflammation also triggers a variety of stop signals that serve to actively terminate the reaction 

switch in the type of arachidonic acid metabolite produced, from proinflammatory leukotrienes to anti-inflammatory lipoxins

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liberation of anti-inflammatory cytokines, including transforming growth factor-β (TGF-β) and IL-10, from macrophages and other cells

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production of anti-inflammatory lipid mediators, called resolvins and protectins, derived from polyunsaturated fatty acids

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neural impulses (cholinergic discharge) that inhibit the production of TNF in macrophages

 Chronic Inflammation o Occurs when inflammation is prolonged or when there is interference to healing o Results into replacement of normal tissue by a fibrous connective tissue = scarring  Tissue Repair o substitution of viable cells for dead cells o by regeneration or replacement o Which will occur depends on:  Type of cell involved  Severity of the injury  Type of inflammation o

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Cells can be classified into 3 types based on their ability to produce new cells: 1. Labile cells 2. Stable cells 3. Permanent cells Generally, the more severe the injury is, the more likely replacement will take place. Tissue repair involves o Clot formation o Inflammation o Formation of granulation tissue o Regeneration or replacement of tissues -

in severe wounds, wound contracture can occur

 Adaptive Immunity  The adaptive immune system is a functional system that: o Recognizes specific foreign substances o Acts to immobilize, neutralize, or destroy foreign substances o Amplifies inflammatory response and activates complement  The adaptive immune system is antigen-specific, systemic, and has memory  It has two separate but overlapping arms: o Antibody-mediated (humoral) immunity (provided by antibodies in the blood and lymph) o Cell-mediated immunity (lymphocytes are involved)

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Antigens are large molecules that stimulate an adaptive immune system response Foreign antigens are not produced by the body (self-antigens are) B cells are responsible for antibody-mediated immunity T cells are involved with cell-mediated immunity

 Activation of Lymphocytes 

The antigenic determinant (epitope) is the specific part of the antigen to which the lymphocyte responds

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The antigen receptor (T-cell receptor or B-cell receptor) on the surface of lymphocytes combines with the antigenic determinant

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MHC class I molecules display antigens on the surface of nucleated cells, resulting in the destruction of the cells

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MHC class II molecules display antigens on the surface of antigen-presenting cells, resulting in the activation of immune cells

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MHC antigen complex and co-stimulation are usually necessary to activate lymphocytes

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Co-stimulation involves cytokines and certain surface molecules

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Antigen-presenting cells stimulate the proliferation of helper T cells which stimulate the proliferation of B or T effector cells

 Antibody-Mediated Immunity 

Antibodies are proteins

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The variable region of an antibody combines with the antigen

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The constant region activates complement or binds to cells

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Five classes of antibodies exist: IgG, 1gM, IgA, IgE, and IgD

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Antibody Production

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The primary response results from the first exposure to an antigen

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B cells form plasma cells, which produce antibodies and memory B cells

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The secondary response results from exposure to an antigen after a primary response

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Memory B cells quickly form plasma cells and additional memory B cells

 Cell-Mediated Immunity  Cells infected with intracellular microorganism’s process antigens that combine with MHC class I molecules  Cytotoxic T cells are stimulated to divide, producing more cytotoxic T cells and memory T cells, when MHC class I/antigen complexes are presented to T-cell receptors  Cytokines released from helper T cells also stimulate cytotoxic T cells  

Cytotoxic T cells lyse virus-infected cells, tumor cells, and tissue transplants Cytotoxic T cells produce cytokines, which promote phagocytosis and inflammation

 DISORDERS OF THE IMMUNE SYSTEM  3 BROAD CATEGORIES: o Hypersensitivity Reactions o Autoimmune diseases o Immunologic deficiency syndromes  HYPERSENSITIVITY REACTIONS 1. Immediate Hypersensitivity  IMMEDIATE (TYPE I) HYPERSENSITIVITY  Rapidly developing immunologic reaction occurring within minutes after the combination of an antigen with antibody bound to mast cells in individuals previously sensitized to the antigen  Mediated by IgE antibodies directed against specific antigens (allergens)  Mechanism:  Ag + Ab (IgE) bound to mast cells / basophils  immediate release of vasoactive amines and other mediators from mast cells; recruitment of inflammatory cells  ANTIBODY-MEDIATED (TYPE II) HYPERSENSITIVITY  Mediated by antibodies against intrinsic antigens or extrinsic antigens adsorbed on cell surfaces or ECM.  Mechanism  Ab (IgG or IgM) + Ag (bound to cell surface or ECM

ANTIBODY-MEDIATED (TYPE II) HYPERSENSITIVITY- DISORDERS

TARGET ANTIGEN

DISEASE

MECHANISM

Autoimmune hemolytic anemia

RBC membrane proteins

IIa Opsonization and phagocytosis of erythrocytes

Autoimmune thrombocytopenic purpura

Platelet membrane proteins (GpIIb:IIIa or GpIb/IX)

IIa Opsonization & phagocytosis of platelets

Good pasture syndrome

Non-collagenous protein in BM of alveoli and glomeruli

IIb complement and Fc receptor mediated inflammation

Myasthenia gravis

Acetylcholine receptor

IIc Ab inhibits Ach binding; down regulates receptors

Graves’ disease (hyperthyroidism)

TSH receptor

IIc antibody-mediated stimulation of TSH receptors

Insulin-resistance DM

Insulin receptor

IIc Ab inhibits binding of insulin

 IMMUNE-COMPLEX MEDIATED (TYPE III) HYPERSENSITIVITY  Mechanism: Ag + Ab AgAb complex (in circulation or in situ)  activate complement attract neutrophils  release lysosomal enzymes  Systemic or local  PHASE I o Formation of Ag-Ab complexes in the circulation  PHASE II o Deposition of the immune complexes in various tissues  PHASE III o Inflammatory reaction at the sites of immune complex deposition o Clinical features appear

DISEASE

ANTIGEN INVOLVED

MANIFESTATIONS

SLE

DNA, nucleoproteins, others

Nephritis, arthritis, vasculitis

Polyarteritis nodosa

Hepa B surface Ag’s

Vasculitis

Post streptococcal glomerulonephritis

Streptococcal cell wall antigen(s); may be “planted in GBM

Nephritis

Acute glomerulonephritis

Bacterial, parasite, tumor antigens

Nephritis

Arthus reaction

Various foreign proteins

Cutaneous vasculitis

Serum sickness

Various proteins (e.g. foreign serum)

Arthritis, vasculitis, nephritis

 T-CELL MEDIATED (TYPE IV) HYPERSENSITIVITY  Initiated by antigen-activated (sensitized) lymphocytes A. Delayed type hypersensitivity- CD4+ T cells o Principal pattern of response to TB, fungi, protozoa, and parasites, as well as contact skin sensitivity and allograft rejection o Released Cytokines: o IFN ‫ﻻ‬-activation of macrophages o IL2- proliferation of T-cells o TNF and lymphotoxin- extravasation of lymphocytes and monocytes; granuloma formation B. T-cell mediated cytotoxicity- CD8+ T cells o Response to viral infections and tumor cells, may contribute to graft rejection o Mediated by 2 pathways (1) perforin-granzyme-dependent killing (2) Fas-fas ligand– dependent killing 2. Cytotoxic (Antibody-Mediated) Hypersensitivity A. Opsonization and Complement and Fc receptor-mediated phagocytosis B. Complement and Fc receptor mediated inflammation C. Antibody mediated cell dysfunction 3. Immune Complex Mediated Hypersensitivity 4. Cell Mediated Hypersensitivity A. Delayed type hypersensitivity B. T-cell mediated hypersensitivity

 MECHANISMS OF IMMUNOLOGICALLY MEDIATED DISEASES PROTOTYPE DISORDER

TYPE

IMMUNE MECHANISMS

I

Immediate hypersensitivity

Anaphylaxis; allergies, bronchial asthma (atopic forms)

Production of IgE Abs  immediate release of vasoactive amines and other mediators from mast cells

II

Antibody-mediated

AIHA (IIa)

Production of IgG, IgM  binds to Ag on target cells or tissue  phagocytosis or lysis of target cell by C8,C9 (IIa), or inflammation (IIb) or cellular dysfunction (IIc)

Good pasture syndrome IIb) Graves, Myasthenia Gravis (IIc)

III Immune complex mediated

SLE, some forms of GN, serum sickness, Arthus reaction

Deposition of Ag-Ab complexes  complement activation  recruitment of leukocytes release of lysosomal enzymes and toxic moieties

IV Cell-mediated hypersensitivity

Tuberculosis (IVa)

Activated T ;lymphocytes  i) release of cytokines and macrophage activation; ii) T cellmediated cytotoxicity

Response to viral infections (IVb) Transplant rejection

 AUTOIMMUNE DISEASE o Result from tissue injury caused by T cells or antibodies that react against self-antigens

 SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Clinical Features: 1.

Female > male (10:1 – 20:1)

2.

2nd – 3rd decade: acute o

Older patients: less acute and better prognosis

3. Most common signs and symptoms: (a) Hematologic – 100% (b) Musculo-skeletal (arthritis)- 90%

(c) Skin (Butterfly rash)- 85% (d) Fever- 83% (e) Renal, Pulmonary, Cardiac- 30-50% 4. Course: o o

Acute: death within weeks to months Chronic: with treatment, 10-20 years

5. Some factors related to pathogenesis: A. Genetic B. Environmental C. Immunologic

 IMMUNODEFICIENCY DISEASES A. 1. Primary: almost always genetically determined; usually x-linked, seen during infancy (6mos – 2 years); associated with recurrent infections 2. Secondary: result from altered immune function: malnutrition, viral infection/irradiation, use of immunosuppressive drugs, lymphoproliferative diseases B. Based on primary components: 1. Stem cell deficiency 2. B-cell deficiency 3. T-cell deficiency 4. Deficiency of myeloid elements 5. Complement deficiency  ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) 1. Etiology  HIV1 – U.S., Central Africa, Europe, Asia  HIV2 – West Africa 2. Epidemiology a. Risk Groups: - homosexuals or bisexual males - IV users - hemophiliacs - blood transfusion recipients - heterosexual contacts b. Transmission: - sexual contact

- parenteral - infected mother to newborn 3. Pathogenesis a. 2 major targets of HIV: immune system & CNS b. immunologic alterations - loss of CD4+ T-cells (Helper cells), macrophages infected - abnormalities of B-cell function 4. Clinical Features  young homosexual or IV drug abuser, (+) HIV Ab test  early and middle phase: acute symptoms or generalized-lymphadenopathy  Late: “AIDS indicator diseases” INFECTIONS: opportunistic Pneumocystis carinii pneumonia Fungal infections NEOPLASMS: Kaposi sarcoma B-cell Non Hodgkin lymphoma Primary lymphoma of the brain Invasive cancer of the uterine cervix  DISORDERS OF THE IMMUNE SYSTEM 3 BROAD CATEGORIES: o Hypersensitivity Reactions o Autoimmune diseases o Immunologic deficiency syndromes o Amyloidosis

IMMUNO-SEROLOGY NOTES  Auto Immunity 1. Auto or Self antigens o Antigens present in one’s own cells o Altered by the action of bacteria, viruses, chemicals or drugs as a non-self 2. Auto antibody o Altered cell (Auto Ag) - elicits the productions of Antibody 3. Auto Immunity (misnomer, alternative= auto allergy) o Immune response of auto Ab against self Ag o Humoral or cell mediated immune response against the constitutes of the body’s own tissues. o There are more than 80 different kinds of diseases caused by autoimmunity.

 Autoimmune Diseases o Autoimmune diseases are a group of disorders in which tissue injury is caused by humoral (by auto-antibodies) or cell mediated immune response (by auto-reactive T cells) to self-antigens. o Normally, the immune system does not attack the self. However, there is a large group of autoimmune diseases in which the immune system does attack self-cells...