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IMMUNODEFICIENCY

IMMUNODEFICIENCY. LANGE CHAPTER 68 DR SAMUEL AGUAZIM. Immunodeficiency can occur in any of the four major components of the immune system 1. B-cells 2. T- cells 3. Complement 4. Phagocytes Note: recurrent infection or opportunistic infections are commonly seen. B cell Deficiencies.

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IMMUNODEFICIENCY

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  1. IMMUNODEFICIENCY LANGE CHAPTER 68 DR SAMUEL AGUAZIM

  2. Immunodeficiency can occur in any of the four major components of the immune system • 1. B-cells • 2. T- cells • 3. Complement • 4. Phagocytes • Note: recurrent infection or opportunistic infections are commonly seen.

  3. B cell Deficiencies • Bruton’sagammaglobulinemia • The basic defect in X-Linked Agammaglobulinemia is a failure of B-lymphocyte precursors to mature into Blymphocytes • Pre mature to mature B cells and ultimately plasma cells. Since they lack the cells that are responsible for producing gamma globulins, these patients have severe deficiencies of gamma globulins. • Molecular defect: mutant tyrosine kinase

  4. Patients with X-Linked Agammaglobulinemia (XLA) are prone to develop infections because they lack antibodies. • The infections frequently occur at or near the surfaces of mucus membranes, such as the middle ear, sinuses and lungs, but in some instances can also involve the bloodstream

  5. Clinical features recurrent infections involving the ears, sinuses, nose,bronchi and lungs -pneumonia ( Haemophilusinfluenzae, pneumococci, and staphylococci). Malabsorption -1 Celiac disease , lactase deficiency Giardiasis Autoimmune Pernicious anemia

  6. Selective IgA Deficiency • Most common of the primary immunodeficiency diseases • Individuals with Selective IgA Deficiency are deficient in IgA but usually have normal amounts of the other types of immunoglobulins • IgA deficient patients may be relatively well with very mild, if any, clinical illnesses while others may be affected by a variety of significant clinical problems.

  7. Severe combined immunodeficiency • This is a rare syndrome of diverse genetic causes in which there is combined absence of T lymphocyte and B-lymphocyte function. • Deficiency of Adenosine Deaminase: The absence of this enzyme leads to an accumulation of toxic metabolic by-products within lymphocytes that cause them to die

  8. CLINICAL PRESENTATION: common symptom in infants with SCID is an excessive number of infections. Pneumocystiscarinii chickenpox virus (varicella). Fungal (yeast) infections-thrush-candida • Rx……. Intravenous immunoglobulin (IVIG) replacement therapy should be given to SCID infants. • Gene therapy • bone marrow • or cord blood transplantation.

  9. ThymicAplasia(DiGeorge Syndrome) • Failure of third pharyngeal pouches to develop with subsequent absence of all four parathyroid glands and thymus • Parathyroid gland abnormalities hypoparathyroidism –hypocalcemia-tetany • Heart defects-truncusarteriosus • deficiency in their T-lymphocyte number and function

  10. Chronic Mucocutaneous Candidiasis • In this disease, the skin and mucous membranes of children are infected with C. albicans, which in immunocompetentindividuals is a nonpathogenic member of the normal flora. These children have a T-cell deficiency specificallyfor this organism; other T-cell and B-cell functions are normal. Treatment consists primarily of antifungal drugs.

  11. The X-linkedHyper IgM syndrome • Deficiency of CD40 ligand T-lymphocytes are unable to instruct B-lymphocytes to switch their production of gammaglobulins from IgM to IgG and IgA • As a result, patients with this primary immunodeficiency disease have decreased levels of serum IgG and IgA and normal or elevated levels of IgM Increased susceptibility to infection.

  12. Interleukin-12- Receptor Deficiency • Patients with a deficiency of IL-12 receptor have disseminated mycobacterialinfections. The absence of the receptor prevents IL-12 from initiating a Th-1 response, which is required to limit mycobacterial infections.

  13. COMBINED B CELLS AND T CELL DEFICIENCIES • A. SEVERE COMBINED IMMUNODEFICIENCY DISEASE(SCID) • B. WISKOTT ALDRICH SYNDROME • C. ATAXIA TELANGIECTASIA

  14. Disorders of lymphoid stem cells: SCID • Defects in both humoral and cellular mediated immunity • 1: 100,000 births • Lack of lymphoid cells: thymus, peripheral lymphoid organs • Death due to infections at 1 yr of age

  15. SCID FORM X-linked recessive type • Most common SCID • Abnormal IL receptors • Normal B cells, low to absent T cells, low NK cells • Treatment: bone marrow transplant

  16. David Vetter: the BUBBLE BOY

  17. David Vetter: the BUBBLE BOY

  18. SCID Forms Autosomal recessive type -deficiency of adenosine deaminase (ADA) or purine nucleotide phosphorylase (PNP) -accumulation of toxic metabolites in lymphocytes - impaired DNA synthesis -treatment: gene therapy

  19. WISKOTT-ALDRICH SYNDROME • Recurrent pyogenic infections, eczema, and bleeding caused by thrombocytopenia characterize this syndrome • X-linked recessive • DEFECTIVE WASp : CYTOSKELETAL REORGANIZATION • INITALLY NORMAL T CELL NUMBERS, THEN REDUCES TOWARDS ADULTHOOD • LOW IgM • PLATELET DEFECT, LOW COUNT • The most important defect is the inability to mount an IgM response to the capsular polysaccharides of bacteria, such as pneumococci.

  20. WISKOTT-ALDRICH SYNDROME • TRIAD: thrombocytopenic purpura ezcema recurrent infections (encapsulated bacteria)

  21. WISKOTT-ALDRICH SYNDROME • Male infants with WAS usually present with bleeding bloody diarrhea prolonged bleeding from circumcision, purpura, or unusual bruising • Treatment: steroids antibiotics immunoglobulins

  22. Ataxia-telangiectasia • breakage in chromosome 14 • deficiency of T cells • lack of coordination of movement (ataxis) • dilation of small blood vessels of the facial area (telangiectasis) • It is an autosomal recessive disease caused by mutations in the genes that encode DNA repair enzymes. • IgG and IgA are considerably reduced • high incidence : leukemias

  23. COMPLEMENT DEFICIENCIES A. HEREDITARY ANGIOEDEMA This is an uncommon autosomal dominant disease caused by a deficiency of CI inhibitor. In the absence of inhibitor, C1 continues to act on C4 to generate C4a and subsequently additional vasoactive components such as C3a and C5a. This leads to capillary permeability and edema in several organs. Laryngeal edema can be fatal. Steroid drugs, such as oxymetholone and danazol, can be useful in increasing the concentration of Cl inhibitor.

  24. RECURRENT INFECTIONS • Patients with deficiencies in C I, C3, or C5 or the later components C6, C7, or C8 have an increased susceptibility to bacterial infections. • Patients with C3 deficiency are particularly susceptible to sepsis with pyogenicbacteria such as S. aureus. • Those with reduced levels of C6, C7, or C8 are especially prone to bacteremiawith Neisseriameningitidis or Neisseriagonorrhoeae.

  25. AUTOIMMUNE DISEASE • Patients with C2 and C4 deficiencies have diseases resembling systemic lupus erythematosus or other autoimmune diseases. C2 deficiency is the most common complement defect and is frequently asymptomatic.

  26. PAROXYSMAL NOCTURNAL HEMOGLOBINURIA • Characterized by episodes of brownish urine(hemoglobinuria) particurlarly upon arising. • Etiology: This is caused by an acquired deficiency of decay-accelerating factor (DAF) on the surface of blood • cell precursors, leading to an increased activation of complement

  27. Phagocyte deficiencies • CHRONIC GRANULOMATOUS DISEASE • MUTATION OF THE CYBB GENE ON THE X-CHROMOSOME-80% • DEFECT IN NADPH OXIDASE • INABILITY TO PRODUCE PEROXIDES AND SUPEROXIDES that kill the organisms. • RECURRENT INFECTIONS WITH CATALASE (+) ORGANISMS: Staphylococcus

  28. CHRONIC GRANULOMATOUS DISEASE • first 5 years of life • Most commonly involved: skin lungs GI tract lymph nodes liver and spleen • GIT, GUT GRANULOMA

  29. CHRONIC GRANULOMATOUS DISEASE

  30. CHRONIC GRANULOMATOUS DISEASE

  31. CHRONIC GRANULOMATOUS DISEASE • NITROBLUE TETRAZOLIUM TEST • BLUE FORMAZAN • CGD : (-) BLUE INCLUSIONS IN PHAGOCYTES

  32. Treatment • DAILY TMP-SMZ 160/800 MG TAB BID PO • ITRACONAZOLE 200MG QID PO • PREDNISONE • STEM CELL TRANSPLANT

  33. CHEDIAK-HIGASHI DISEASE • AUTO RECESSIVE , DEFECT IN CHS1 GENE • DEFECTIVE NEUTROPHILS: DEFECTIVE MICROTUBULES REDUCED INTRACELLULAR KILLING POOR CHEMOTACTIC MOVEMENT

  34. CHEDIAK-HIGASHI DISEASE • AFFECTS SYNTHESIS/STORAGE OF SECRETORY GRANULES IN VARIOUS CELLS Lysosomes of leukocytes and fibroblasts • azurophilic granules of neutrophils • melanosomes of melanocytes

  35. OCULOCUTANEOUS ALBINISMNYSTAGMUS (PERIPHERAL NEUROPATHY) INCREASED SKIN INFECTIONS

  36. Treatment • BONE MARROW TRANSPLANT • MICROTUBULE DRUGS • ACYCLOVIR • IG

  37. JOB'S SYNDROME (HYPER-IGE SYNDROME) • Patients with this syndrome have recurrent "cold"1 staphylococcal abscesses, eczema, skeletal effects, and high levels of IgE. • The main immunologic defect is a failure to produce gamma interferon by helper T cells, which reduces the ability of macrophages to kill bacteria

  38. LEUKOCYTE ADHESION DEFICIENCY SYNDROME • Patients with this syndrome have severe pyogenic infections early in life because they have defective adhesion (LFA-1) proteins on the surface of their phagocytes. • This is an autosomal recessive disease in which there is a mutation in the gene encoding the f3 chain of an integrin that mediates adhesion. As a result, neutrophilsadhere poorly to endothelial cell surfaces and phagocytosis of the bacteria is inadequate.

  39. Acquired immunodeficiences • Common Variable Immunodeficiency is a disorder From mature B cells to Immunoglobulin • characterized by low levels of serum immunoglobulins (antibodies) and an increased susceptibility to infections

  40. In some patients there is a decrease in both IgG and IgA; in others, all three major types (IgG, IgA and IgM) of immunoglobulin's may be decreased. • B-lymphocytes fail to undergo normal maturation into plasma cells capable of making the different types of immunoglobulin's and antibodies. • patients lack the helper T-lymphocytes necessary for a normal antibody

  41. MALNUTRITION • Severe malnutrition can reduce the supply of amino acids and thereby reduce the synthesis of IgG. This predisposes to infection by pyogenic bacteria.

  42. T-Cell Deficiencies • ACQUIRED IMMUNODEFICIENCY SYNDROME • Patients with acquired immunodeficiency syndrome (AIDS) present with opportunistic infections caused by certain bacteria, viruses, fungi, and protozoa • This is due to greatly reduced helper T-cell numbers caused by infection with the retrovirus human immunodeficiency virus

  43. B.MEASLES • Patients with measles have a transient suppression of delayed hypersensitivity as manifested by a loss of PPD skin test reactivity. Quiescent tuberculosis can become active. In these patients, T-cell function is altered but immunoglobulinsare normal.

  44. Complement Deficiencies • A. LIVER FAILURE • Liver failure caused by alcoholic cirrhosis or by chronic hepatitis B or hepatitis C can reduce the synthesis of complement proteins by the liver to a level that severe pyogenic infections can occur.

  45. B. MALNUTRITION • Severe malnutrition can reduce the supply of amino acids and thereby reduce the synthesis of complement proteins by the liver. This predisposes to infection by pyogenic bacteria.

  46. Phagocyte Deficiencies • A. NEUTROPENIA • Patients with neutropenia present with severe infections caused by pyogenic bacteria such as S. aureus and S. pneumoniaeand enteric gram-negative rods. • Neutrophilcounts below 500/4 predispose to these infections. • Common causes of neutropenia include cytotoxicdrugs, such as those used in cancer chemotherapy;leukemia, in which the bone marrow is "crowded out“ by leukemic cells; and autoimmune destruction of the neutrophils. • Ciprofloxacin is used to try to prevent infections in neutropenic patients.

  47. Chronic Fatigue Syndrome (ChronicFatigue Immune Dysfunction Syndrome) • The predominant finding in patients with chronic fatigue syndrome (CFS) is persistent, debilitating fatigue that has lasted for at least 6 months and is not relieved by bed rest

  48. B-Cell Deficiency Disorders 50

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