Primary Immunodeficiency Disorders Inherited or congenital and are generally rare

Defects causing primary immune deficiencies may occur in : the combined lymphoid cell lineage, T- or 8-cell lineages separately, Lineages producing phagocytic cells and natural killer (NK) cells, and even Cells producing complement components Autosomal gene defects affect both sexes equally. However, defective X-linked genes affect males far more frequently than females.

Pleuripotent stem cells that generate granulocytic, erythrocytic, monocytic, thrombocytic, and lymphocytic lineages of the hematopoietic system are initially found in the aorta-gonad­ mesonephros of the developing embryo. 2 migrations : fetal liver and bone marrow Lymphoid system cells generate B cells (B-1 and B-2) and T cells . Defects in stem cells B2 cell lineage remains within the bone marrow for development B1 lineage relocates to and self replicatesin the peritoneal/pleural tissues, and the T-cell lineage migrates to the thymus.

Defects in lymphoid stem cells give rise to both the T and B cell lineages result in defective function of both cell types Individual defects may result in abnormal T and B cell numbers or functions or both. Cell mediated responses are usually reduced as in immunoglobulin production.

Stem cell defects Adenosine deaminase (ADA) deficiency Immunodeficiency with ataxia telangiectasia Purine nucleoside phosphorylase deficiency Severe combined immune deficiency (SCID) Wiskott-Aldrich syndrome Stem cell defects

Defects in the combined lymphocytic lineage (loss of B and T cell systems) A group of diseases caused by different defects in individual genes that have similar functional consequences. SCID

Defects in T cells Abnormal T-cell numbers and/or functions Delayed type hypersensitivity response is largely responsible for clearance of fungi, frequent or recurrent fungal infections are suggestive of defects in T-cell function Secondary category of T-cell defects comprises those in which the responsible mutation are not limited to T cells but may occur in cells that are critical to the developent or activation of T cell Some T cell defects arise from mutations in other cells that influence the developent or activation of T cells. Defects in T cells T cell help is critical to the activation of naïve and memory B cells.

T cell defects CD3 deficiency DiGeorge syndrome MHC class II deficiencies (bare lymphocyte syndrome) Purine nucleoside phosphorylase deficiency Transporter associated with antigen presentation (TAP)- 1 or -2 deficiency ZAP-70 deficiency T cell defects DiGeorge syndrome or congenital thymic aplasia is a t-cell deficiency that is due to the failure of the thymus to develop normally during embryogenesis. Cell mediated immune responses are undetectable.

Defects in B cells Autosomal recessive agammaglobulinemia X-linked (Bruton) agammaglobulinemia (XLA) Common variable immunoodeficiency (CVI or CVID) Immunodeficiency with hyper-IgM ( X-linked hyper- IgM / XHIM) Ig heavy chain gene deletions Kappa chain deficiency Selective IgA deficiency Defects in B cells XLA is due to mutations in the Bruton tyrosine kinase gene which is important for B cell receptor signalling. They lack mature B cells, plasma cells and all 5 classes of AB XHIM is characterised by high levels of serum IgM and very low levels of serum IgG,A and E. B cells function normally. T helper cells lack a ligand important for signalling to the B cells to undergo isotype switching and generate memory B cells. CD 4o ligand is important for T cell interaction with dendritic cells and macrophages. Selective IgA deficiency is the most common primary immunodeficiency disorder characterised by a reduced level of IgA in the presence of normal levels of the other Ab isotypes.

Defects in phagocytes and natural killer cells Defects in nonlymphocytic cells such as phagocytes, neutrophils and NK cells. Defects in phagocytic cells are significant because of their key roles in both innate and adaptive immune responses Affects Ability to kill microbes Interactions with other cell types Defects in phagocytes and natural killer cells

Defects in phagocytes and NK cells Chronic granulomatous disease (CGD) Chédiak_Higashi syndrome IFN- gamma receptor deficiency Leukocyte adhesion defect 1 (LAD-1) Leukocyte adhesion defect 2 (LAD-2) Defects in phagocytes and NK cells CGD involved the inheritance of defects in nicotinamide adenine dinucleotide phosphate oxidase which is esential for the production of the reactive oxygen species during respiratory burst that accompanies phagocyte activation. LAD is a group of rare inherited disorders that is due to the defect in adhesion molecules of neutrophils and often other leukocytes that are necessary for leukocytes to enter the tissue from the blood.

Defects in complement system Affect innate and adaptive immune responses C1q, C1r deficiency C2/3/4/5/6/7/8/9 deficiency Factor H/P deficiency Hereditary angioedema Paroxysmal nocturnal hemoglobinuria Defects in complement system Complement component c3 is common to all pathways of complement activation and as such, deficiencies in c3 have the most dramatic effect. Patients lacking in c6-c9 components are unable to form Membrane attack complex. However they are competent for opsonic function, immune clearance and initiating inflammation via complement cascase.