Disorders of Immune System

- Hypersensitivity Reactions:

Immune response to exogenous antigens

- Autoimmune diseases:

Immune reactions against self antigens

- Immune deficiency syndromes

Congenital / acquired

- Amyloidosis

Hypersensitivity reactions

- Group of immune reactions resulting from exposure to

exogenous antigens

- Designed as a protective response but usually results in

tissue injury

- Caused by mixture of humoral and cell mediated reactions

- Classified into 4 types based on immunologic basis

Hypersensitivity reactions

- Type I (Immediate) hypersensitivity

- Type II (antibody mediated) hypersensitivity

- Type III (immune complex mediated) hypersensitivity

- Type IV (cell mediated) hypersensitivity

Type I Hypersensitivity Reaction:

- Rapidly developing immunologic reaction

- Occurs within minutes of antigen-antibody reaction

- Antibody is bound to surface of sensitized mast cells

- Antigen is called allergen and reaction is called allergy

- Reaction may be localized or systemic

- Release of vasoactive and spasmogenic substances

Local reaction:

Depends on the point of entry of allergen

- Localized cutaneous swellings (skin allergy, hives)

- Nasal / conjunctival discharge (allergic rhinitis / conjunctivitis)

- Hay fever, bronchial asthma (respiratory allergy)

- Allergic gastroenteritis (food allergy)

Local reaction:

Depends on the point of entry of allergen

- Localized cutaneous swellings (skin allergy, hives)

- Nasal / conjunctival discharge (allergic rhinitis / conjunctivitis)

- Hay fever, bronchial asthma (respiratory allergy)

- Allergic gastroenteritis (food allergy)

Systemic

- Follows injection of allergen

- Produces state of shock within minutes

Elements that participate in Type 1 hypersensitivity:

- B and T lymphocytes

- Antigen presenting cells

- Mast cells & Basophils

- IgE antibodies

- Chemical mediators

Mast cells:

- Bone marrow derived, widely distributed in tissues

- Contain cytoplasmic membrane bound mediator granules

- Have high affinity IgE Fc receptors

- Also triggered by complement C5a and C3a (anaphylotoxin)

- Responsible for allergic reactions in tissue

Mediators:

Primary: Secondary

- Histamine - Phospholipids

- Proteases (PGD2, Leukotrienes)

- Chemotactic factors - Platelet activating factor

- Cytokines

Action Mediator

Vasodilation, Increased vascular permeability

HistaminePAFLeukotrienes C4, D4, E4Neutral proteases (activate complement)PGD2

Smooth muscle spasm

Leukotrienes C4, D4, E4HistamineProstaglandinsPAF

Cellular infiltration

Cytokines TNFLeukotriene B4Eosinophil and Neutrophil chemotactic factorsPAF

Local hypersensitivity reactions

- Immediate phase (initial response):

Vasodilation and vascular leakage, smooth muscle contraction

Starts 5-30 minutes and subsides in 1 hour

Vasoactive amines are responsible

- Second phase (Late response):

Tissue infiltration by inflammatory cells including eosinophils

Starts 2-24 hrs and lasts for many days

Other mediators including cytokines

Major cause of symptoms in asthma etc. Inflammatory response

is sustained without further antigen exposure

Type I Hypersensitivity may be genetically determined

(ATOPY)

Atopic individuals have higher levels of serum IgE

Family history of allergy is seen in 50% atopic individuals

Antibody mediated (Type II) Hypersensitivity

- Antibody directed against antigens present on cells and tissues

- Antigen may be self or of external origin (drug metabolite)

- Basis for many auto immune diseases

Mechanisms

1a) Opsonization and complement and Fc receptor mediated phagocytosis

Mechanisms

1a) Opsonization and complement and Fc receptor mediated phagocytosis

1b) Complement mediated lysis of opsonized cells (C5-9) (MAC)

1c) Antibody dependent cellular toxicity (ADCC)

Antibody mediated cell destruction and phagocytosis

- Blood transfusion reactions

- Erythroblastosis fetalis

- Autoimmune hemolytic anemia, agranulocytosis, thrombocytopenia

- Drug induced hemolytic anemia

Mechanisms

2) Complement and Fc Mediated inflammation

- Antibody deposited in extracellular tissues

- Complement activation (C5a)

- Inflammatory cells recruited, activated

- Enzymes and reactive oxidative metabolites

- TISSUE INJURY

Causes- Glomerulonephritis- Vascular rejection- Acute rheumatic fever

Mechanisms3) Antibody mediated cellular dysfunction

Antibody binds to cell surface

receptors and disrupts function

Myasthenia gravis,

Pemphigus vulgaris

Antibody binds to cell surface

receptors and stimulates function

Graves disease

Type III Hypersensitivity (immune complex mediated)

- Antigens and antibodies form complexes either in circulation of locally

in tissues (Antigen may be exogenous (foreign protein, bacteria, virus)

or endogenous (ones own))

- The complexes get deposited in tissues

- Inflammatory reaction is initiated resulting in tissue damage

- May be generalized (serum sickness) or localized (arthus reaction)

Serum sickness

- Injection of horse serum into humans (passive immunization)

- Antibodies (preformed / new) against horse proteins

- Antigen Antibody complexes deposit in tissues

- Fever, skin rash, arthritis, nephritis

- Resolution following clearing of complexes

- Chronic exposure / re-exposure --------------------------

Arthus reaction: Local antigen stimulus in a sensitized individual

Arthus reaction: Local antigen stimulus in a sensitized individual

Arthus reaction: Local antigen stimulus in a sensitized individual

Morphologic consequences:

- Fibrinoid necrosis of blood vessels

- Proliferative glomerulonephritis

- Arthritis

Vasodilation and edema

Neutrophil and monocyte infiltrate

Necrosis