Immunology and Serology notes 2- Complement, Autoimmunity and Hypersensitivity PDF

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Summary

Immunology and Serology notesCOMPLEMENT SYSTEM Produces a cascade phenomenon where the product of one reaction is enzymatic catalyst of the nextHALLMARKS Heat lability (destroyed when heated at 56’C for 30mins  Cytolytic activity  Only IgM and IgG can activate the complementFUNCTIONS Activation...

Description

Immunology and Serology notes COMPLEMENT SYSTEM 

Produces a cascade phenomenon where the product of one reaction is enzymatic catalyst of the next

HALLMARKS   

Heat lability (destroyed when heated at 56’C for 30mins Cytolytic activity Only IgM and IgG can activate the complement

FUNCTIONS   

Activation of the immune system Opsonization (C3b) Cell lysis (C5b6789)

SUMMARY OF PROTEINS INVOLVED 1. Classical- C1 through C9 2. Alternate- Factor B, Factor D, C3 through C9 REGULATORY PROTEINS 1. 2. 3. 4. 5. 6. 7. 8.

C1 inhibitor Factor 1 cleaves C3b and C4b Factor H cofactor with I to inactivate C3b; prevents binding of B to C3b C4- binding protein acts a cofactor with I to inactivate C4b S protein (vitronectin)- prevents attachment of the C5b67 complex to all membranes CD59 (membrane inhibitor of reactive lysis)- blocks assembly of MAC Homologous restriction factor- binds to C8 therefore prevents formation of MAC Decay accelerating factor- prevents assembly of C3 convertase

CLINICAL SIGNIFICANCE OF COMPLEMENT Deficiency C1 INH C1 (q, r, or s) C2

C4

Disease Hereditary Angioneurotic Edema (HANE) Lupus like syndrome Lupus like syndrome; recurrent infections, atherosclerosis Severe recurrent infections, glomerulonephritis Lupus like syndrome

C 5,6,7,8 C9- enhances lysis CD59/MIRL Delay accelerating factor Homologous restriction factor

Recurrent infections with Neisseria spp. No known disease association Paroxysmal nocturnal hemoglobinuria Paroxysmal nocturnal hemoglobinuria Paroxysmal nocturnal hemoglobinuria

C3

TUMOR MARKERS TUMOR MARKER AFP (alphafeto protein) Amylase CA-125 CA-15.3 CA-19.9 Calcitonin CEA Estrogen receptor Nuclear matrix protein PSA HCG – human chronic gonadotrophin

ASSOCIATED CANCER Hepatic and testicular cancers Pancreatic cancer Ovarian cancer (treatment and recurrence) Breast cancer ( treatment and recurrence) Pancreatic cancer Medullary thyroid cancer Colorectal cancer Breast cancer Urinary bladder cancer Prostate cancer Nonseminomatous testicular cancer, choriocarcinoma

AUTOIMMUNITY 

a result of breakdown in self-tolerance that leads to the immune system responding to self-molecules as if they were foreign.

DISORDER Type 1 diabetes

Rheumatoid arthritis

PATHOLOGY Selective destruction of the insulin producing B cells of the islets of Langerhans in the pancreas Chronic systemic inflammatory disorder in which joint

ANTIBODIES Anti-glutamic acid decarboxylase (GAD) antibodies Anti-insulin antibodies Rheumatoid factor: IgM or IgG Antibodies specific

HLA correlation HLA-DR3 HLA-DR4

HLA-DR4

Systemic lupus erythematosus

Pernicious anemia

Myasthenia gravis

Scleroderma

Sjogren’s syndrome

cartilage, ligaments, and tendons are destroyed Immune complexes are formed and lodge in the basement membrane of kidney, skin and joints Destruction of the parietal cells of the stomach mucosa leading to intrinsic factor deficiency Neuromuscular transmission disorder due to antibodies that inhibit and block acetylcholine binding skin fibroblast reproduce faster and secrete more collage Presence of rheumatoid factor and anti-nuclear antibodies are indicative of a systemic disease with many tissues involved

for Fc region of IgG

Anti-nuclear antibodies

HLA-DR2 HLA-DR3

Anti-extractable nuclear antibodies Anti-parietal cell antibodies Anti-intrinsic factor antibodies Antibodies specific for acetylcholine receptor

HLA-B8

HLA-DR3 (weak)

HLA-DR3

IMMUNOPROLIFERATIVE DISORDERS 1. Monoclonal gammopathy  A benign or malignant condition that results from a single clone of lymphoid-plasma cells producing elevated levels of a single class of and type of immunoglobulin, referred to as a monoclonal protein, M protein or paraprotein. A. Multiple myeloma- plasma cells neoplasm resulting in overproduction of immunoglobulins. IgG gammopathy. B. Waldenstrom’s macroglobulinemia- infiltration of lymphoplastic cells in the bone marrow. IgM gammopathy. C. Monoclonal gammopathy of undetermined significance (MGUS)- presence of monoclonal proteins with no features of multiple myeloma or Waldenstrom’s macroglobulinemia. D. Light chain disease E. Heavy chain disease- failure to make light chains resulting in overproduction of heavy chains. 2. Polyclonal Gammopathy  Consist of one or more heavy chains classes and both light chain types.

IMMUNODEFICIENCY DISORDER Immunodeficiency: failure of the immune system to protect against disease or malignancy. Primary immunodeficiency: due to genetic or developmental defects of the immune system. Secondary or acquired immunodeficiency: loss of immune system due to exposure to disease agents, immunosuppressant or aging.

PHAGOCYTES QUALITATIVE DEFECTS DISEASE Myeloperoxidase deficiency Chediak-higashi syndrome

Job’s syndrome Lazy leukocyte syndrome Leukocyte adhesion deficiency Chronic granulomatous disease (CGD)

UNDERLYING DEFECT Deficiency in myeloperoxidase which is an important microbicidal agent in neutrophils Impaired chemotaxis and phagosome degranulation Presence of giant cytoplasmic granules Neutrophils demonstrate defective chemotaxis Defective chemotactic response by neutrophils Lack of CD18 X-linked recessive disorder Defect in NADPH oxidase system Reduced intracellular killing of ingested organisms

B-Cell Deficiency Disorders DISEASE Bruton’s X-linked aggamaglobulinemia

Selective Ig deficiency (Dysgammaglobulinemia) Selective IgA deficiency Transient hypogammaglobulinemia

UNDERLYING DEFECT Genetic defect in the long arm of X chromosome Block in the maturation of pre B cells Low serum levels of immunoglobulin and lack of B cells Arrest in the development of B cells is the culprit Most common form of selective Ig deficiency Results when the onset of Ig synthesis is delayed

T- cell Deficiency Disorders DISEASE DiGeorge syndrome Chronic cutaneous candidiasis Bare lymphocyte syndrome

DEFECT Associated with defect of chromosome 22 Impaired synthesis of macrophages inhibitions by T cells Deficiency in the expression of MHC II gene products on the T cell surface leading to failure of antigen presentation

COMBINED B CELL AND T CELL DISORDDERS DISEASE Severe combined immunodeficiency disease

Nezelof’s syndrome

Wiskott Aldrich syndrome Ataxia Telangiectasia

X linked Lymphoproliferative disease

DEFECT Combined defect of both humoral and cell mediated immunity Autosomal recessive type is associated with adenosine deaminase deficiency Rarely survive beyond age 1 if no treatment Thymic dysplasia resulting in decreased to absent T cell immunity Usually have marked lymphadenopathy and hepatosplenomegaly Deficiency in dense granules Mutation in the WASP protein gene Result of specific genetic defect that affects DNA repair Sinupulmonary infection Mutation in SH2DAI/SAP gene resulting in weakening of both cellular and humoral immunity Vulnerability to EBV infection

HYPERSENSITIVITY 

A normal but exaggerated or uncontrolled immune response to an antigen that can produce inflammation, cell destruction or tissue injury.

CLASSIFICATION OF HYPERSENSITIVITY REACTIONS Reaction Complement Antibody mediating Cells involved

Mechanism of tissue injury Examples

Type I Anaphylactic

Type II Cytotoxic

No IgE

Yes IgG/IgM

Mast cells/ basophils

Host tissue cells; RBC, WBC, platelets Cytolysis due to antibodies and complement Transfusion reactions HDN Autoimmune HA

Allergic and anaphylactic reactions Hay fever Asthma Food allergies

Type III Immune complex Yes IgG/IgM

Type IV T cell dependent No None

Neutrophils, monocytes

T cells

Immune complex deposition SLE Post strep GN Serum sickness

Release of cytokines Contact dermatitis Mantoux reaction to TB...