Ø  Antibody (Humoral) mediated immunity- extracellular bacteria or bacterial products

Ø  Cell Mediated Immunity (CMI)- primarily operates against intracellular viral, bacterial, as well as fungal antigens

Ø  “DOUBLE-EDGE SWORD”- in most cases your immune system is protective, but it can also be destructive.

Ø  Immunopathology- tissue damage resulting from the immune response

• allergies, hypersensitive reactions, autoimmune disorders

Seven Immune Mechanisms

• remember Gell and Coombs first classified as type I-IV reactions

Antibody Mediated

1-inactivation or Activation     -Toxin, virus inactivation

2-Cytotoxic or cytolytic    Type II    – Opsonization, ADCC, C’-mediated lysis

3-Immune Complex   Type III  -Ag-Ab complex formation in tissue

4-Atopic or Anaphylactic  reactions (common)    Type I   -IgE mediated allergic reactions

Cell-mediated

5-T-cell Cytotoxic (T_CTL­)   -Lysis of virus-infected cells; contact hypersensitivity

6-Delayed Hypersensitivity (T_DTH)   – Type IV    – CD4+ T cell-mediated activation of macrophages

Either

7-Granulomatous Reactions     – Chronic rxn to poorly degradable Ags

In vitro (in a tube) mechanisms seen in immune reactions are similar to those seen in vivo (in life).

• Primary reactions consist of Ag-Ab complexes or Ag-TCR
• Secondary reactions are effects of those in vitro
• Tertiary reactions are the in vivo manifestation

Induction of Different forms of immunity

1.     Type of agent or antigen

• intracellular pathogens- CD8 or T_CTL
• extracellular pathogens- CD4 (TH₁ or TH₂) and  Ab responses

2.     Route of infection or exposure

• Mucosal- IgA or IgE
• Intramuscular injection- IgG

3.     Activation of TH₁ or TH₂ cells

• TH₁- favors DTH, IgG
• TH₂- favors IgE and mast cell, basophils, eosinophil activation

4.     Location/cell type involved in Ag presentation

• activation of TH₁ or TH₂ depends on APC or location
• Follicular dendritic cells in B cell follicles favors IgG stim by TH₁
• Langerhans cells or interdigitating cells in cortex of lymph nodes favors DTH responses by TH₁

5.     Genetic factors

• individual variation to Ag exposure
• usually due to different MHC types

6.     Non-Genetic factors

• age, nutrition, etc. also determine strength and type of response

REMEMBER: responses to an Ag are rarely, if ever, of a single type or response.

Functional Diversity of  CD4- T_HELPER cells in response to microbial infections

• can produce many different cytokines to assist in many ways in the immune response

TH₁ INF-g                IgG₁ and IgG₂ B-cell differentiation, mac activ., TH₂ inhibition

IL-2, INF-g       Promotes differentiation of CD8- T_CTL­

TH₂ IL-4                  IgE, IgG₄ B-cell diff.

IL-5                  IgA B-cell diff.

IL-10                Inhibits TH₁ cells

IL-13                IgE production (B-cell diff.)

IL-4, 10, 13      Inhibit inflammation

Antibody mediated immune mechanisms

• Binding of epitope to Ab resulting in inactivation, neutralization, or abnormal activation

Mechanisms

1.     Proteins- Ab can bind and cause steric inhibition due to a conformational change.

2.     Viruses- Ab can bind to virus receptor proteins on the surface of the targeted cell or even the virus and can alter viral structure, interfere with binding, or allow complement or Ab mmediated opsonization and clearance

3.     Sometimes, Ab can bind to hormone or neurotransmitter receptors which can block or activate the receptor.

Medical Aspects

1.     Protection

• immunizations (DT)lead to production of Ab which bind to the toxins in the immunization mixture and prevent them from causing a clinical illness.
• Viral infection or immunization (inc. polio, mumps, rubella, measles, influenza) results in Ab that bind to viral receptors and prevent infections upon subsequent exposures

Immunopathology of Ab mediated immune reactions

1.     Myasthenia Gravis- autoimmune Ab to acetylcholine receptors which inhibits muscular contraction (skeletal)

2.     Graves disease- Ab against the TSH receptor —– activates the thyroid and produces an abnormal amount of T₄ and T₃;  remember no TSH detectable usually due to feedback inhibition (Oh that’s Neuro)

3.     Pernicious Anemia- Ab against intrinsic factor interfere with its binding to B₁₂ in the GI tract

Cytotoxic Reactions (Type II hypersensitivity)  know these are called Type II

• reaction of Ab with cell surface Ag may result in the destruction of cells by opsonization, complement activation, or Antibody Dependent Cellular Cytotoxicity (ADCC)

Mechanisms

1.     Complement Activation- can lyse bacteria directly through the MAC (Membrane Attack Complex)

• remember you have to have one IgM or 2 IgGs bound to the Ag in order to activate the classical pathway.

2.     Macrophage or Neutrophil phagocytosis- can be enhance through Ab binding with Fc receptors or through fixation of C3b

3.     ADCC- results from IgG-mediated binding of null lymphocytes to target cells via Fc receptors which leads to direct killing

4.     IgE-mediated binding or eosinophils to helmiths in poarasitic infections-leads to eosinophil degranulation and damage to the worm tegument.

Medical Aspects

1.     Protection

• This is the primary immune response to BACTERIAL INFECTIONS
• Gram + are very susceptible to Complement mediated killing/opsonization; especially pyogenic bacteria like staph and strept in which you would see massive accumulations of neutrophils
• PROTOZOAL INFECTIONS-  Ab and C’ mediated MAC formation and opsonization are effective against some
• ADCC can be effective against virally-infected cells, tumor cells, protozoa, and helmiths

Immunopathology

1.     Transfusion reactions- ABO mismatches are rapidly lysed due to anti-A or anti-B isohemagglutinins (IgM’s that activate complement)

2.     Rh reactions- hemolytic disease of the newborn; “blue baby”; birth of Rh+ to Rh- sensitized mother

3.     Hemolytic anemia- autoantibodies can cause erythrocyte lysis—-anemia

4.     Goodpasture’s syndrome- gives ribbon-like appearance to glomeruli and other tissues; due to autoantibodies to basement membrane components and complement

Immune Complex Reactions (Type III hypersensitivity) Know this is type III

• formation of soluble or insoluble Ag-Ab complexes that can be deposited in tissue, leading to attraction of PMNs, inflammatory changes, and tissue damage.

Mechanisms

1.     As you increase the concentrations of Ag-specific Ab (IgG and IgM) you form immune complexes

2.     Size of immune complexes depends on cross-linking which depends on antigen excess, quivalence, and Ab excess.

3.     Some immune complexes can fit into complement, resulting in binding of C3b and release of C3a and C5a—chemotaxis—-local mast cell degranulation and attraction of neutrophils—-inflammation

4.     Large immune complexes are usually phagocytosed by certain phagocytic cells like resident macrophages of the reticuloendothelial system

5.     Smaller complexes can become lodged in the walls of venules, joints, and glomeruli.  This causes complement activation, attraction of neutrophils, and release of lysosomal contents which can result in vasculitis, reactive arthritis, and glomerulonephritis.

6.     LUMPY-BUMPY- due to uneven distribution of immune complexes-complement act-and erythema, edema, and attraction of neutrophils

7.     Arthus reaction-  injection of an Ag to a previously sensitized individual results in this due to deposition of Ag-Ab complexes and the whole sha-bang.  Usually takes 2-6 hours to develop.

Medical Aspects

1.     Protection

• Pyogenic infections- immune complexes attract neutrophils which causes a acute inflammatory response;  once bacteria are killed by  phagocytosis and release of their lysosomal contents, the accumulation of dead bacteria, neutrophils, and other cells killed by the bacterial toxins, and fibrin accumulate forming pus.   This reaction can wall off the infection.

Immunopathology

1.     Serum Sickness- serum from horses immunized with rabies virus was used which results in the formation of immune complexes which led to the -itis problems.  Now we use hyperimmune human serum antibodies which has eliminated this problem

2.     Rheumatic fever- infection with Strept. pyogenes can result in formation of  Ab cross-reactive with heart Ag and circulating immune complexes. This can cause heart and kidney damage and vasculitis in other tissues.

Anaphylactic or Atopic Reactions (Type I hypersensitivity) know this is type I

• IgE-mediated activation of mast cells and other cell types
• also calle Type I hypersensitivity or Allergic reactions
• Anaphylactic= away from protection

Mechanisms

1.     Requires production of IgE which is called reagin or Reaginic antibody

• remember isotype switching to IgE requires TH₂ production of IL-4
• IL-6 further enhances prod. of IgE
• Some people can have high levels of certain IgE’s and are thus called sensitized

2.     Most IgE is bound to surface of mast cells or basophils;  it’s not free

3.     Cross-linking must occur; IgE-Ag binding causes decrease in cyclic AMP levels and thus mast cell ACTIVATION,  which leads to rapid degranulation.

• here you have de novo synthesis of arachadonic acid,  which is converted to leukotrienes, PGs, and thromboxanes

4.     Quickly thereafter, you get a wheal and flare reaction if cutaneous or hayfever syndrome if respiratory.

• Histamine- binds to histamine receptors H1—smooth muscle contraction and increases vascular permeability—- also binds to H2—-vasodilation and mucus secretion
• Eosinophil chemotactic factor (ECF-A)- attracts eosinophils
• Neutrophil chemotactic factor (NCF)- attracts neutrophils
• Heparin- anti-coagulant; not directly involved in anaphylaxis
• Wheal and Flare- local erythema (due to vasodilation) and edema (due to increased vascular perm)
• Hayfever- increased mucus secretion; mucosal swelling
• Prausnitz-Kustner reaction- passive cutaneous anaphylaxis due to experimental ingection of IgE into skin

5.     When severe, can cause shock or airway obstruction.

6.     Leukotrienes cause long term smooth muscular contraction which cannot be alleviated by antihistamines.  Can cause some manisfestations of asthma

7.     Prostaglandins promote bronchoconstriction, vasodilation, and chemotaxis of granulocytes

8.     Eosinophils attracted to the area  have IgE bound which can be cross linked to an Antigen and thus cause release of granule contents

• Major Basic Protein- damages parasites; contributes to asthma

9.     Long-acting cells and substances contribute to late phase reactions including asthma

You can reduce the effect of anaphylactic reactions by:

1.     avoiding allergens

2.     drugs (cromolyn Na, corticosteroids, antihistamines, epinephrine)

3.     hyposensitization- long term injection of Ag to get IgG response

4.     desensitization- short term injection of Ag to deplete IgE

Medical Aspects of Anaphylactic or Atopic reactions

1.     Protective

• Helmith infections- IgE-mediated though to aid in the killing of worms.

Immunopathology

1.     Hay fever- allergic reactions to allergens, i.e. pollen, causing increased nasal secretions and watery eyes

2.     Asthma- more sever respiratory reaction; bronchoconstriction; Increased mucus secretion; can be life threatening

3.     Cutaneous anaphylaxis- insect bites

4.     Food allergies-

5.     Systemic anaphylaxis- hypersensitive individuals which develop vascular shock and respiratory failure as a result of exposure to an allergen.  Can be reversed by quick administration of epinephrine.

Tags: Ag, Antibody Mediated, Antibody mediated immunity, bacterial products, either, extracellular bacteria, Follicular dendritic cells, fungal antigens, Granulomatous Reactions, immune mechanisms, Immunopathology, Langerhans cells, pathogens, TH1, TH2

This entry was posted on Tuesday, February 24th, 2009 at 5:36 am and is filed under Immunology. You can follow any responses to this entry through the RSS 2.0 feed. Responses are currently closed, but you can trackback from your own site.