Immuno deficiency diseases- primary and secondary

includes immunodeficiency diseases and its classification

1. Learning objectives Types of immunodeficiencies Primary secondary Classification of primary immunedeficiencies Secondary immune deficiencies AIDS

2. Immunodeficiency deficiency diseases are conditions where the defense mechanisms of the body are impaired . Deficiencies of defense mechanisms may involve SPECIFIC IMMUNE FNS – humoral immunity,cell mediated immunity or both – or NON SPECIFIC MECHANISMS such as phagocytosis & complement, which augment and act in conjunction with specific immune processes .

3. Immuno deiciencies primary immunodeficiencies secondary immunodeficiencies Primary ID - results from abnormalities in the development of immune mechanisms Secondary ID – are consequences of disease,drugs,nutritional inadequacies

4. PRIMARY IMMUNE DEFICIENCIES HUMORAL DEF. CELLULAR DEF. COMBINED

5. Classification of primary immunodeficiencies 1.HUMORAL IMMUNODEFICIENCIES A.DISORDERS OF SPECIFIC IMMUNITY

6. 2.CELLULAR IMMUNODEFICIENCIES

7. 3.COMBINED IMMUNODEFICIENCIES

8. B. DISORDERS OF COMPLEMENT

9. C. DISORDERS OF PHAGOYTOSIS

10. 1.HUMORAL IMMUNODEFICIENCIES A.DISORDERS OF SPECIFIC IMMUNITY

11. X LINKED AGAMMAGLOBULINEMIA First immunodeficiency disease to have been recognised . Described by BRUTON ( 1952 ) . Due to B ruton T yrosine K inase mutation Seen only in MALE infants . Manifestations not apparent till about 6 months of age . 1. NAÏVE B CELLS PLASMA CELLS IgG,IgM,IgA,IgE BTK

12. Clinical pesentation : Recurrent serious infns ( pneumococci,streptococci,meningococci,pseudomonas & h.influenzae ) No tonsils or palpable lymph node

13. Avoid Live microbial vaccines All classes of immunoglobulins are grossly depleted in serum . IgG level being less than a tenth,IgA and IgM less than a hundredth of the normal level . Marked decrease in proportion of B cells in circulation. CMI not affected . MX : 300mg/kg of gammaglobulin per kg of bodyweight in 3 doses foll . by monthly injns of 100mg/kg .

14. Transient hypogammaglobulinemia of infancy Due to abnormal delay in the initiation of IgG synthesis in some infants . Presents b/w 6 -12 months of age . When there is a delay, immunodeficiency occurs . Recurrent otitis media & respiratory infectios are common . Spontaneous recovery occurs b/w 18 & 30 months of age . Found in infants of both sexes . Rx : may be req in some cases, but prophylactical administration not recommended . 2. M = F

15. Common variable immunodeficiency Late onset hypogammaglobulinemia . Manifests only by 15 – 35 years of age . Recurrent pyogenic infections and increased incidence of autoimmune diseases . Malabsorption and giardiasis are common . Total immunoglobulin level is less than 300mg/100ml,with IgG < 250mg/100ml . B cells present in circulation in normal numbers, but they appear defective in their inability to differentiate into plasma cells and secrete immunoglobulins . RX : administration of gammaglobulin preparation intramuscularly/intravenously. 3.

16. X – LINKED AGAMMAGLOBULINEMIA COMMON VARIABLE IMMUNOGLOBULIN DEFICIENCY HUMORAL HUMORAL PRESENT AFTER 6 MONTHS ADOLOSCENCE ABSENT ANTIBODIES LOW ANTIBODIES ( VARIABLE LEVELS ) ABSENT TONSILS NORMAL SIZE TO LARGE TONSILS

17. Selective immunoglobulin deficiencies Selective deficiency of one or more immunoglobulin classes. These dysgammaglobulinemias are common. Isolated IgA deficiency is the most common . Often accompanied by atopic disorders . Increased susceptibility to respiratory infection & steatorrhea . Selective IgM deficiency has been ass with septicemia . Selective IgG deficiency has been ass with c/c progressive bronchiectasis . 4.

18. immunodeficiencies with hyper i g M XL , AR . Low IgA & IgG , IgE levels are seen with elevated IgM . Mutations in the genes that code for CD40 LIGAND IgM molecules appear to have normal structure and possess antibody activity . Enhanced susceptibility to infns & autoimmune processes such as thrombocytopenia,neutropenia,hemolytic anemia & renal lesions. Some develop malignant infiltration with IgM producing cells. DD : Congenital Rubella RX: IgG REPLACEMENT THERAPY 5.

19. TRANSCOBALAMIN II DEFICIENCY AR Pts show metabolic effects of vit B12 def. including megaloblastic anemia and intestinal villous atrophy . Immunological defects : depleted plasma cells,diminished immunoglobulin levels, impaired phagocytosis . Rx : vit B12 . 6 .

20. General presentation T – CELL DEFECTS B – CELL DEFECTS PRESENT AFTER BIRTH PRESENT AT 6 MONTHS OR OLDER COMBINED DEFECTS ARE MORE SEVERE VIRAL INFNS FUNGAL INFNS MYCOBACTERIA PCP BACTERIAL INFNS PROTOZOAL INFNS ENTERO VIRUS

21. 2.CELLULAR IMMUNODEFICIENCIES

22. THYMIC HYPOPLASIA/DIGEORGE SYNDROME Failure of the third and fourth pharyngeal pouch . Due to 22 q 11 mutation Lack of thymus  T cell deficiency Lack of parathyroid  hypocalcemia Abnormalities of heart,great vessels Abnormal facial features 1.

23. CHRONIC MUCOCUTANEOUS CANDIDIASIS Abnormal immunological response to candida albicans . Severe chronic candidiasis of mucosa,skin & nails. No increased susceptibility to other infns . CMI to candida is deficient. 2. RX Transfer factor therapy along with Amphotericin B

24. PURINE NUCLEOSIDE PHOSPHORYLASE DEFICIENCY AR Decreased CMI Recurrent or chronic infns Low serum uric acid points to the diagnosis 3. Hypoplstic anemia Recurrent pneumonia Diarrhoea Candidiasis

25. 3.COMBINED IMMUNODEFICIENCIES

26. CELLULAR IMMUNODEFICIENCY WITH ABNORMAL immunoglobulin SYNTHESIS (NEZELOF SYNDROME) Group of disorders Depressed CMI with selectively elevated,decreased or normal levels of immunoglobulin Marked T cell def with varyind B cell def . In spite of normal level of Igs,antigenic stimuli do not induce ab fmn . 1. Recurrent fungal,bacterial & viral infns Rx BMT Transfer factor Thymus transplantn Antimicrobials

27. ATAXIA TELENGIECTASIA AR Ataxia telengiectasia mutated (ATM ) gene at 11q22 - 23 23 ( AUTOSOMAL RECESSIVE ) . Affects T and B cell . Thymic hypoplasia CLINICAL PRESENTATION Ataxic gait in second yr of life . Inability to ambulate independently @ 10 yrs of age . Telengectasia ( dilated blood vessels ) . Ovarian dysgenesis Risk of malignancy 2. Diagnosis ELEVATED AFP DECR. IgA AND IgE MRI: CEREBRAL ATROPHY & VENTRICULAR ENLARGEMENT Rx IVIG ANTIBIOTICS

28. WISKOTT ALDRICH SYNDROME XLR ONLY BOYS Mutn IN WASp COMMON PRESENTATION Eczema Bloody diarrhea Atopic dermatitis Infn with encapsulated bacteria 3. Eczema Thrombocytopenia Small platelets Recurrent infns – T cells affected Diagnosis Decr . T cell number & function Low IgM Prenatal- CVS - amniocentesis Rx Skin care IVIG and/or corticosteroids Platelet transfusion splenectomy

29. A ATAXIA TELENGECTASIA FRIEDREICH’S ATAXIA AR AR Chr 11 CHR 9 Ataxia Ataxia Age 1 yr Age 8 -15 yrs require wheel chair by 10/11 yrs Loss of ambulation 15 yrs after the onset intact sensation & negative rhombergs sign Spinal or sensory ataxia & positiv rhombergs sign telengectasia No T& B cells affected No

30. B. DISORDERS OF COMPLEMENT

31. Complement component deficiencies AR Freq ass with SLE Recurrent pyogenic infns with C3 deficiency Neisserial infns with C6,C7 & C8

32. Complement inhibitor deficiencies AD Hereditary angioneurotic edema – C1 inhibitor def Chronic recurrent pyogenic infections – C3b inactivator def

33. C. DISORDERS OF PHAGOYTOSIS

34. C/C GRANULOMATOUS DISEASE & myeloperoxidase deficiency AR XLR NBT

35. Chediak higashi syndrome

36. Clinical features AR Albinism,photophobia,nystagmus Frequent and severe pyogenic infns Mild bleeding diathesis Recurrent infections DIAGNOSIS LARGE CYTOPLASMIC GRANULES( IB ) IN ALL NUCLEATED CELLS GRANULES ARE PEROXIDASE POSITIVE RX BMT

37. LEUCOCYTE G6PD DEFICIENCY Leucocytes deficient in gluc 6 phosphate dehydrogenase Diminished bactericidal activity after phagocytosis NBT test normal JOB’S SYNDROME Primary defect in phagocytic function Serum immunoglobulins normal except for IgE TUFTSIN DEFICIENCY Prone to local & systemic bacterial infns LAZY LEUCOCYTE SYNDROME Basic defect in chemotaxis and neutrophil mobility. HYPER IgE SYNDROME Cellular and humoral immune mechanisms are normal But IgE levels aremore

38. SECONDARY IMMUNODEFICIENCIES CAUSES MALNUTRITION MALIGNANCY INFECTIONS MATABOLIC DISORDERS CYTOTOXIC DRUGS / IMMUNOSUPPRESSIVE AGENTS AGEING

39. DEFICIENCIES in humoral and cellular immune responses occur secondarily during course of many disease processes . Secondary immune deficiency is more common than the primary immune deficiency AIDS, Aquired immune deficiency syndrome is the most common . Humoral deficiency  lymphoid malignancy ( CLL )  nephrotic syndrome  exfoliative skin disease  protein losing enteropathioes  multiple myeloma Cellular deficiency  lymphoreticular malignancies  lymphatic obstruction or lymphorrheas  lepromatous leprosy  measles

40. aids HIV 1 Infects helper T cells (TH ) cells Normal count – 1200/mm³ Aids - < 200/mm³ of blood Monocytes also get infected .

41. RX HIV ANTIVIRALS

42. SUMMARY Primary immunodeficiencies present more common in children & adoloscents . In general secondary immunodeficiencies afe more common <6 MNTS, FTT, C/C DIARRHOEAEA ABSENT TONSILS & THYMUS >6 MONTHS ABSENT TONSILS,LNs BOYS ADOLOSCENCE Low Igs NORMAL TONSILS RECURRENT INFECTIONS SCID X-LINKED AGAMMAGLOBULINEMIA CVID

43. RECURRENT INFNS Staph aureus Pneumatocele Coarse facial features Eczema PCP infns Mouth ulcers Neutropenia Recurrent gi infns Recurrent sinusitis Low IgA Hyper IgE syndrome Hyper IgM syndrome IgA deficiency

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