Immunodeficiency: Primary immune deficiency: -Caused by intrinsic or congenital defects.-Over 100 diseases of this type are known in humans, and for many of these diseases, the specific defective genes have been identified.-Types: 1-Defects in stem cells.2-Defects in T lymphocytes.3-Defects in B lymphocytes.4-Defects in phagocytes and NK cells.5-Defects in complement system.

Defects in stem cells:1-Severe combined immune deficiency (SCID): Genetics:

Mode of Inheritance: Autosomal recessive (chrom. 11).

X-linked recessive.

Defective genes: RAG 1,2 gene.

IL2RG gene.

Function: Rearrangement of DNA to form variable

regions of Immunoglobulin and TCR.

Production of γ chain (common cytokine receptor)

: IL-2R, IL-4R, IL-9R, IL-15R, INF γR.

N

Effect: Defect in B and T lymphocytes maturation. Features: Lethal susceptibility to both viral and bacterial infections due to deficiency of both humoral and cellular immunity.

2-Ataxia telangiectasia: Genetics: AR -Rearrangement of gene at chromosome 7, 14. -Gene: T cell receptor genes. -Function: T lymphocyte clonal selection.

N

Feature: -Oculocutaneous telangiectasia (dilated blood

vessels in the conjunctivae, ears, and face.(

-Low serum IgA, and IgG.

-Thymus hypoplasia.

- Recurrent infection: Sinusitis, and pneumonia. - Increased risk of Leukemia and Lymphoma.

N

3-Wiskott-Aldrich syndrome:Genetics: - XR gene mutation.- Etiology: defect in lymphocyte cytoskeleton.

Feature:

Boys have eczema, diarrhoea and recurrent infections,

thrombocytopenia, low IgM level, and Tc -Th function.

Defect in T Lymphocytes: 1-bare Lymphocyte syndrome: Genetics: AR gene on Chromosome 1 or 16.

Etiology:

Type 1: Mutation in the TAP gene prevent export of

Class I MHC to the cell surface .

Type 2 : Defects in MHC II specific transcription factor, cause defect in T-helper function.

Features:

- Increased susceptibility to infection.

- CD4 and CD8 cells numbers decreased .

- Intracellular infection could cause lethal effect.

N

2- DiGeorge syndrome: Genetics:

AD gene deletion in chromosome 22 q 11 .

Etiology :

1 -Complete or partial absence of thymus.

2 -Defect in T-cell clonal selection and maturation.

Features:

- Increased susceptibility to viral infection.

- Reduced active T cell production.

Defect in B Lymphocytes:

1- Bruton’s agammaglobulinaemia: Genetics: X-linked recessive gene (BTK).

Etiology:

Defective B-cell tyrosine kinase prevents the B cell maturation.

Features:

-Increased susceptibility to infection (capsulated bacteria).

-Very low level of Immunoglobulin or lost level .

-5-6 months boys develop lethal multiple infections of lung.

N

2-Immunodeficiency with Hyper-IgM: Genetics : X-linked recessive gene (CD40L G).

Etiology: 1-Defect in expression of CD40L on B lymphocyte.2-Inability of B lymphocyte to undergo isotype switching.

Features:-Elevated IgM and IgD in blood stream.-Decreased IgG, IgA, and IgE concentration.-Increased susceptibility to pyogenic infection.

N

3-Selective IgA deficiency: Genetics: Multiple genes and forms. Etiology: -Defect in IgA production in body fluids. Features: -No increased susceptibility to infection. -Low IgA level. -Normal level of other antibodies.

Defect in Phagocytes and Natural Killer cell:

1-Chronic granulomatous disease (CGD): Genetics: -XR ;Beta-chain of cytochrome b oxidase. -AR (chr.1,7); NADPH oxidase. -AR (chr.16); alpha chain of cytochrome b oxidase.

Etiology: -Inability of Phagocytes to generate superoxide metabolites.

Features: -Granulomatous infection in skin, lymph nodes, lung, liver.

N

2-Chediak- Higashi syndrome: Genetics: -AR (Chromosome 1) Gene (LYST). (Lysosomal trafficking regulator).

Etiology: -Defect in fusion of lysosome to phagosomes. -Defect of release of cytotoxic granules.

Features:-Increased susceptibility to pyogenic bacteria.-Reduced ability of phagocytes to kill ingested microbes. - Decreased functions of NK cell (Cytotoxicity). -Risk for development of Lymphoma.

N

3- Leucocyte adhesion deficiency: Genetics: AR gene (ITGB2 or CD18) The leukocyte surface integrin Beta chains.

Etiology: -Defect in migration of WBCs from circulation to the site of infection (tissue). Features: -Increased susceptibility to infection. -Frequent abscesses. -Defective chemotaxis.

Defect in complement system :1- C1,2,3,…,9 immunodeficiency: Genetics: Autosomal recessive gene (Chr. 1,2,5,6,9,12,19). Etiology: C1,2,3,...,9 deficiency.

Features: -Increased susceptibility to infection. -associated with lupus like syndrome. -Defect in production of MAC unit of Classical pathway.

N

2-Hereditary angioneurotic edema: Genetics: Autosomal dominant gene (Chr. 11). C1 inhibitor protein.

Etiology: Defect in inhibition of Classical pathway.

Features: - Fluids accumulation in soft tissue and airways due to

uncontrolled production of C2a.

-Swelling of tracheal and bronchial passages that can be

life-threatening.

Secondary (acquired) immune deficiency:

-The immunodeficiency that associated with exposure to environmental factors.-Not related to inheritance of genetic mutations.

-Types: 1-Therapeutic immunodeficiency.

2-Malignant tumor- associated deficiency.

3-Infectious immunodeficiency.

N

Therapeutic immunodeficiency:Examples:

-Some Anti-inflammatory drugs (corticosteroids)

; treatment of Rheumatoid arthritis :

Interfere with production of some cytokines.

-Immunosuppressive drugs (cyclosporine); used during

organ transplantation:

Interfere with production of some cytokines.

N

Malignant tumor- associated deficiency: Examples:-Multiple myeloma: Increased polyclonal B cell activation non-specifically.

- Lymphoma (HK):

Uncontrolled proliferation of B lymphocytes (E.B virus).

-Chronic lymphocytic leukemia:

Reduced production of Immunoglobulin.

Infectious immunodeficiency:Examples:-Schistosoma species: Enzymatic degradation of immunoglobulins.-Herpesvirus: inhibits MHC class I maturation within E.R.

-CMV: Interferes with TAP of E.R. Redirects MHC I into cytoplasm rather than to cell surface. -Chlamydia: prevents phagosomes-lysosomes fusion.

N

-Staphylococcus: -Kills phagocytes by its toxins. -Protein A prevents opsonization. -Mycobacterium: -Kills phagocytes. -Prevents phagosome-lysosome fusion. -Inhibits oxidative degradation within phagosome.-Plasmodium species: -RBCs infection. -Human Immunodeficiency virus (HIV): -Kills CD4, Monocytes, and CD8 cells. -Nef gene redirects MHC I into lysosome.

N

Human Immunodeficiency Virus (HIV):HIV infection in humans is considered pandemic by the World

Health Organization (WHO) .From its discovery in 1981 to 2006, AIDS killed more than 25

million people.

Tropism:Some immune cells have a specific HIV susceptibility due to presence of specific receptors.

-Macrophages, and dendritic cells carry the chemokine receptor CCR5.

-CD4 T helper cells express the chemokine receptor CXCR4 .

HIV Tropism:N

HIV infection periods:N

N

1-Asymptomatic period: CD4:8 Ratio= 2:1

2-Latency and chronic period : -The virus is preserved in the dendritic cells of Lymph nodes. -Late Latency : CD4:8 Ratio= 1:1

3-AIDS period: -No cytotoxic Tc response.-No Humoral immunity.-CD4:8 Ratio= 1:2-CD4 count less than 200 cell per μL.