1. Inherited Immunodeficiency Disorders

2. The immune system in all its forms is our defense mechanism against the armies of microorganisms, and other infectious agents that, numerically, dwarf the human population.

3. Immune defense mechanisms can be divided into two main types: Innate immunity; which includes a number of non-specific systems that do not require or involve prior contact with the infectious agent Specific acquired or adaptive immunity; which involves a tailor-made immune response that occurs after exposure to an infectious agent.

4. Inherited immunodeficiency disorders are uncommon and severe. Presentation is variable but often in childhood for more severe immune defects, especially after the benefits of maternal transplacental immunity have declined. Investigation of immune function should be considered in all patients with recurrent infectionsand inchildren with failure to thrive.

5. Primary Inherited Disorders of Immunity Disorders of innate immunity Abnormalities of humoral immunity are associated with reduced resistance to bacterial infections and may be lethal in infancy Abnormalities of cell-mediated specific acquired immunity are associated with increased susceptibility to viral infections.

6. Disorders of Innate Immunity Disorders of Innate Humoral Immunity • Disorders of complement Disorders of Innate Cell-mediated Immunity • Chronic granulomatous disease • Leukocyte adhesion deficiency (LAD)

7. Disorders of Complements • Defects of the C3; lead to abnormalities of opsonization of bacteria, resulting in difficulties in combating pyogenic infections • C1 inhibitor deficiencyis an autosomal dominant disorder. C1 inhibitor controls the kinin-bradikinin pathway and its deficiency causes accumulation of bradykinin in the tissues and is believed to be the main cause of edema, triggered by episodes of surgery, trauma or some drugs. Attacks vary from mild cutaneous to potentially fatal laryngeal edema. This is known as HEREDITARY ANGIO-EDEMA. • C2 deficiency is an autosomal recessive disorder. It is associated with cutaneous vasculitis, Henoch-Schönlein purpura, rheumatoid arthritis and systemic lupus erythematosus.

8. Chronic Granulomatous Disease Chronic granulomatous disease (CGD), an inherited disorder of phagocytic cells, results from an inability of phagocytes to produce bactericidal superoxide anions (O2-) that is caused by a defect in phagocytic NADPH oxidase. Patients suffer from life-threatening bacterial & fungal infections. Dramatic inflamatory response leads to granuloma formation. CDG is genetically heterogenous; X-linked recessive (%65-70) : CYBB gene was the first human disease gene cloned by positional cloning Autosomal recessive (%30-35) :

9. Leukocyte Adhesion Deficiency • Autosomal recessive disorder characterized life-threating bacterial infections of the skin, mucous membranes and impaired pus formation • The increased susceptibility to infections occurs because of the defective migration of phogocytes from abnormal adhesion related functions of chemotaxis and phagocytosis. • There are three different forms of LAD • LAD I: ( ITGB2 gene mutation ) • LAD II: (Golgi specific GDP-fructose transporter gene mutation) • LAD III: genetic defect is unkown

10. Disorders of Specific Acquired Immunity Disorders of Humoral Acquired Immunity • Bruton type agammaglobulinemia • Hyper-IgM syndrome • Common variable immunodeficiency (CVID) Disorders of Cell-mediated Acquired Immunity Severe Combined immunodeficiency (SCID)

11. Bruton-type Agammaglobulinemia • X-linked recessive disorder with developmental arrest in B-lymphocyte differentiation • Multiple recurrent bacterial infections of the respiratory tract and skin after the first few months of life !!!! • B cell tyrosine kinase (Btk) gene mutations result in loss of signal for B cells to differentiate to mature antibody-producing plasma cells.

12. Hyper-IgM Syndrome • Genetically heterogeneous syndrome characterized by increased level of IgM and IgD and decreased level or absence of other immunoglobulins. • Patients are susceptible to recurrent pyogenic infections as well as opportunistic infections (Pneumocystis and Cryptosporidium) • X-linked recessive form (HIGM1) ; TNFSF5 gene mutations result with inefficient switching of immunoglobulin classes, so that IgM production cannot be readily switched to IgA or IgG • Autosomal recessive form (HIGM2 –HIGM3): CD40 deficiency – AICDA deficiency

13. Common Variable Immunodeficiency (CVID) • CVID constitutes the most common group of B-cell deficiencies, but is very heterogeneous and causes are unknown. • Selective IgA deficiency is common finding. • Many affected people have no obvious health problems, but others may have recurrent infections, gastrointestinal disorders or autoimmune diseases.

14. Severe Combined Immunodeficiency (SCID) • SCID is characterized by a marked deficiency of both T- and B- lymphocyte function and associated with increased susceptibility to both viral and bacterial infections. • SCID is genetically heterogeneous, can be inherited as either X-linked recessive or autosomal recessive. • X-linked form is is the most common form in males (%50-60). In this form T cell are defective but B cells are normal. • One type of the autosomal recessive forms is due to a deficiency of Adenosine Deaminase (ADA).

15. SCID-ADA deficiency • ADA deficiency is approximately 15% of all SCID and 1/3 of autosomal recessive forms of SCID • Phenotypic spectrum is variable. • The most severe being SCID presenting in infancy and usually resulting early death. • marked deficiency of both T- and B- lymphocyte function (T-B- phenotype) • Treatment • Bone marrow transplant • Continuous enzyme supplement • Gene Therapy !!!!!

16. Secondary or Associated Disorders of Immunity • DiGeorge Syndrome • Wiskott-Aldrich Syndrome • Ataxia Telangiectasia

17. DiGeorge Syndrome • A Chromosomaldisorder (Microdeletionon chromosome 22q11) • Infants with this immunodeficiency have a developmental defect of their 3rd and 4th pharyngeal pouches which affects embryogenesis of parathyroids, thymus and heart. Hypocalcemia Hypoparathyroidism Thymicaplsaia (T-cell deficiency) Tetralogy of Fallot Mental retardation

18. Wiskott-Aldrich Syndrome • X-linked recessive • Gene defect of WASP protein causes cytoskeletal dysfunction • B and T cell dysfunction • Associated Symptoms • Thrombocytopenia –petechiae • Eczema • Hepatosplenomegaly • Autoimmune Hemolytic Anemia • High incidence of lymphoma – CNS

19. Ataxia Telengiectasia • Autosomal Recessive – Chromosomal instability syndrome • Have both B and T cell dysfunction • more characteristics of B cell dysfunction • Associated Symptoms • Ataxia from early age – progressive • Telangiectasia develop after 2 y/o • High risk for various malignancies • Endocrine abnormalities – many w/ Diabetes • Liver Dysfunction