1. Immunodeficiency Disorders מחלות חסר אימונולוגיות

2. Origins of Immunodeficiency Primary or Congenital ראשוני או מולד –Inherited genetic defects in immune cell development or function, or inherited deficiency in a particular immune molecule –פגם גנטי מורש הגורם להתמינות לא תקינה או תפקוד לקוי של תאי מערכת החסון, או נזק למולקולה בעלת תפקוד חסוני. Secondary or acquired –A loss of previously functional immunity due to infection, toxicity, radiation, splenectomy, aging, malnutrition, etc. –נזק למערכת חסון תקינה כתוצאה מהדבקה, רעילות, קרינה, אבוד טחול, גיל, תזונה לקויה ועוד.

3. Primary Immunodeficiencies Primary=Genetically determined More than 100 disorders identified Most are B cell deficiencies –Incidence ranges by disorder IgA deficiency 1:333 Agammaglobulinemia 1:50,000 SCID 1:250,000 Seen more in infants –5:1 male-to-female predominance in children –1:1.4 male-to-female in adults

4. Infectious Consequences of Immunodeficiency משמעות חסר חסוני לגבי הדבקות בפתוגנים Antibody deficiency, Phagocyte deficiencies, or Complement protein deficiencies are associated with recurrent infections with extracellular pyogenic bacteria (pneumonia, otitis media, skin infections) מחסור בנוגדנים, פאגוציטוזה לא תקינה ומחסור בחלבוני משלים, קשורים להדבקות בחידקים חוץ תאיים גורמי מוגלה. Deficiency in Cell-mediated immunity is associated with recurrent or chronic viral, fungal, or protozoal diseases. חוסר של מערכת חסון תאית מלווה בהדבקות חוזרות או כרוניות בוירוסים, פטריות או פתוגנים חד תאיים (למשל טוקסופלסמה).

5. Primary B cell Deficiencies Genetic disorders of the B lymphocytes Approximately 70% of primary immunodeficiencies Not enough Ig or too much Ig X-Linked Agammaglobulinemia (XLA ) Hyper IgM Syndrome Selective IgA deficiency –Occurs in 1:600-1:800 people Development of anti-IgA antibodies may lead to severe anaphylactic reactions with blood transfusions

6. –B cells do not differentiate. Mutation in Bruton’s tyrosine kinase (Btk) required for B cell development. - B cells absent in peripheral blood. - T cell numbers and function are normal –no antibodies are produced, thus no antibody- mediated immunity –cell-mediated immunity is OK –affects males only –Symptoms at 9 mo. to 2 yr of age –Treat with intravenous immunoglobulin (IVIG). X-linked Agammaglobulinemia (Bruton’s Agammaglobulinemia)

7. Hyper-IgM Syndrome A syndrome characterized by very low serum IgG, IgA and IgE but extremely high levels of IgM. X-linked - CD154 (CD40 Ligand) Deficiency Autosomal Recessive -Activation-Induced Cytidine Deaminase Deficiency (AICD)

8. CD154 (CD40 Ligand) Deficiency Diagnosis - Males become symptomatic after 6-9 months. Prone to pneumonia, have profound neutropenia, and very small lymph nodes and tonsils. B cells and T cell numbers are normal. Molecular Defect - mutation in CD154 or CD40 Ligand. - found on the surface of activated helper T cells. Interacts with CD40 on surface of B cells. - Cross-linking of CD40 by CD40L in the presence of cytokines causes B cells to undergo proliferation and isotype switching. Defective T-B interaction in Hyper IgM Immuonodeficiency

9. Activation-Induced Cytidine Deaminase Deficiency (AICD) Autosomal recessive Male and Female Diagnosis - Serum IgG, IgA, and IgE are very low. Serum IgM elevated and polyclonal. -Patients are generally older and not susceptible to pneumonia. -Normal numbers of B cells but are not able to class- switch in presence of T cells Molecular Defect - mutations in activation-dependent cytidine deaminase (AID).

10. Treatment of B cell disorders Agammaglubulinemia - Monthly injections of antibody, intravenous gammaglubin “ IVIG ” Hyper IgM Syndrome - Bone marrow transplant at early age. IVIG, management of infections with antibiotics

11. Immunodeficiency Syndromes

12. T Cell Deficiencies

13. Defect in T Cells Di George ’ s Syndrome (DGS) A disease that results from hypoplasia (partial loss) or aplasia (complete loss) of thymus and parathyroid glands, therefore no T cells. Relatively common (1/4000 live births), affect both male and female Diagnosis - Spectrum of developmental abnormalities: cardiac outflow abnormalities (congenital heart disease), hypoplasia of the parathyroid and thyroid glands, cleft palate and unusual facies. Normal Ig levels. Molecular Defect - Gene Tbx1 (transcription factor) on chromosome 22q11 is defective in most cases. Causes defects in 3rd and 4th pharyngeal pouches during embryogenesis Clinical spectrum and effect on thymus is highly variable Complete (rare) : Severe T cell lymphopenia. Increased susceptibility to pneumonia (P. carinii), oral candidiasis, diarrhea, failure to thrive. Mild (common) : present in adults as chronic sinusitis/ bronchitis

14. Di George ’ s Syndrome Facies: Micrognathia, low set ears, anti-mongoloid slant to eyes, fish-shaped mouth, hypertelorism, narrow philtrum

15. Treatment of Di George ’ s Syndrome Partial form - generally don ’ t need immunological treatment Complete form –Thymic epithelial explants Culture mature thymic epithelial cells and transplant into patient.

16. A fatal syndrome of diverse genetic causes characterized by profound deficiencies in both T and B cells Diagnosis –Early onset <6mos –Frequent episodes of diarrhea, pneumonia, otitis, sepsis, cutaneous infections Molecular Defects –Quite diverse, although several common etiologies occur Common (gamma) chain - X-linked Adenosine Deaminase - a utosomal recessive Jak 3 kinase - a utosomal recessive SCID - Severe Combined Immunodeficiency

17. Some Heteromeric Cytokine Receptors Share at least the  Chain e.g. the IL-2R family utilizes the same  chain.

18. SCID I - Common  chain Most common etiology of SCID - 46% of cases in the US X-linked recessive ONLY in males Abnormal gene was identified as the common  chain that is shared by several cytokine receptors - IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 Lack T cells and NK cells Elevated B cell numbers but are non-functional “ Bubble Boy ” -David Vetter lived for 12 years in a plastic germ-free bubble

19. SCID II - Adenosine Deaminase Deficiency (ADA) Autosomal recessive 15% of US cases ADA is an enzyme that is involved in purine metabolism –Irreversibly deaminates adenosine (nucleoside from food and nucleic acids) converting to inosine by removing amine group Patients get accumulation of adenosine and 2 ’ -deoxyadenosine in thymocytes and peripheral B cells –Inhibits DNA synthesis and leads to destruction of cells Adenosine Inosine

20. SCID III - Deficiencies in Jak-3 Kinase Autosomal recessive JAK-3 kinase is the only known signaling molecule associated with the common  chain No T cells and NK cells B cells present but non-functional

21. Treatment of SCID Bone marrow transplantation Gene therapy –ADA was first genetic defect that was attempted –9 infants received autologous bone marrow that was retrovirally transduced with common  chain –Initially successful-full correction of T and NK cell defect Enzyme replacement therapy –For ADA

22. Phagocyte Deficiencies Chronic Granulomatous Disease –NADPH oxidase defect –Intracellular and extracellular infections, granulomas Chediak-Higashi Syndrome –Abnormal lysosome formation –Intracellular and extracellular infections, granulomas Leukocyte Adhesion Deficiency –Absence of leukocyte adhesion molecules (CD18,  2 integrin) –Defective migration of phagocytes (neutrophils) into infected tissues –Widespread pyogenic bacterial infection

23. Chronic Granulomatous Disease (CGD) Neutrophils require a set of enzymes to produce reactive oxygen species to destroy bacteria after their phagocytosis. Together these enzymes are termed "phagocyte NADPH oxidase" (phox). Defects in one of these enzymes can all cause CGD of varying severity, dependent on the defect. There are over 410 known defects in the enzyme complex Absence of respiratory burst (conversion of intracellular oxygen to hydrogen peroxide, oxidized halogens, superoxide and hydroxyl radicals) in neutrophils and monocytes-impaired bactericidal killing

24. What are Granulomas? Chronic inflammation with a characteristic pattern of a central area of phagocytic cells surrounded by activated lymphocytes. Macrophages fuse to form giant cells in the center Serves to “ wall off ” pathogens that resist destruction. In CGD get continuous granuloma formation because neutrophils cannot clear microbes Nasal inflammation/cellulitis and neck granuloma in an X-linked CGD patient.

25. Leukocyte Adhesion Deficiency Absence of leukocyte adhesion molecules (CD18,  2 integrin) Defective migration of phagocytes (neutrophils) into infected tissues

26. Inherited Immunodefiency: Summary X linked SCID (common gamma chain) T cell deficiency (absence of thymus DiGeorge’s syndrome) Antibody Deficiencies XLA (Btk-/-) Hyper IgM (CD40L-/-) Deficiencies in Phagocytosis/killing: Respiratory Burst (CGD)

27. Diagnosing a primary immunodeficiency 1.Detect a history of recurrent infections 2.Hematology-measures total RBC and WBC cell numbers 3.Facs analysis-determines the numbers of each lymphocyte subset ie. CD4:CD8 T cells, B cells, neutrophils etc. 4.Measurement of serum immunoglobulins 5.Specialized testing 1.T cells-proliferation in response to stimuli 2.B cells-induced antibody production 3.Phagocytes-engulfment 4.Complement-CH 50 the dilution of serum required to lyse 50% of ab-coated RBC

28. Complement Deficiencies Single component deficiencies –Example: C3 deficiency Hereditary Angioedema –C1 Inhibitor deficiency C5,C6,C7,C8, or C9 deficiency –Recurrent bacterial meningitis due defective membrane attack complex

29. Causes of Acquired Immunodeficiency Cancer (immunoproliferative diseases) Cytotoxic drugs or radiation Malnutrition Splenectomy Immunosuppressive therapies Stress/emotions Aging (thymic atrophy) Infection (HIV )

30. Secondary Immunodeficiency's –viral infections many viruses are capable of infecting and killing lymphocytes, thus effectively lowering the immune response human immunodeficiency virus (HIV) infects and destroys T H cells, diminishing both the antibody- mediated and cell-mediated immune systems