2. Pathophysiology of Immunodeficiency Diseases

3. Host Defense Mechanisms
Skin and mucosal barriers
Humoral immunity (B cells, plasma cells, Ab)
Cell-mediated immunity (T cells)
Phagocytosis
Complement

4. Overview of
Immunodeficiency
Disorders.
The defect might be
In the level of
stem cell or
in any other
level of tree

5. Introduction.
Immunodeficiency diseases are : A diverse spectrum of illnesses due to various abnormalities of the immune system
Prevalence :
Primary (congenital) 1 : 10,000 to 1 : 200,000 present at birth .
Secondary (acquired) is more common .

6. Origins of Immunodeficiency
Primary or Congenital
Inherited genetic defects in immune cell development or function, or inherited deficiency in a particular immune component
Secondary or acquired
A loss of previously functional immunity due to infection, toxicity, radiation, splenectomy, aging, malnutrition, etc.

7. (non-specific body defenses). Acquired immunity.
Primary or acquired.
can affect.
Natural immunity
(non-specific body defenses).
Acquired immunity.
(specific body defenses).
Phagocytic
cells.
Complement
proteins.
T-cells.
B-cells.

8. Immunodeficiency / Immunocompromised States
Primary
Intrinsic abnormality of one or more components of the Immune System
>150 Conditions Characterised
Individually, uncommon, but important to recognise
Range from global, overwhelming immune failure ( SCID) to subtle defects in individual components of function
1/ 10,000 live births

9. Suspecting Immunodeficiency
Look for infections that are:
Frequent
Recurrent/chronic
Unusual organisms: aspergillous, nocardia
Organisms that respond poorly to therapy
Unusual site: liver abcess, brain abcess
Severity of infection
Suspecting Immunodeficiency

10. The Ten Warning Signs of Primary Immunodeficiency
8 or more ear infections
within 1 year
2 or more serious sinus infections
2 or more months on
antibiotics without resolution
2 or more pneumonias
Failure to gain weight or grow
normally
Persistent candidiasis
after the age of 1 year
Need for I.V. antibiotic to
clear infections
2 or more deep-seated
infections
A family history of
Primary Immunodeficiency
Recurrent, deep skin or
organ abscesses 1 2 3 4 5 6 7 8 9 10

11. Classification of Primary Immunodeficiency
1. Antibody deficiencies
2. Cellular deficiencies
3. Phagocytic disorders
4. Complement deficiencies
5. Combined Immunodeficiencies

12. HUMORAL Immunodeficiencies (B-cell defects)

13. Antibody deficiencies include:
Common variable immunodeficiency (CVID)
X-linked agammaglobulinemia (XLA)
Selective IgA deficiency (SIgAd)
Selective IgG subclass deficiency (SIgGsd)
Hyper IgM syndrome (HIgM)
Transient hypogammaglobulinemia of Infancy (THI)
Functional antibody deficiency

14. Early B-cell differentiation .
Lesions can occur at any site in the pathway of B-cell development.
B-cell defect could be in any level in the pathway

15. B-cell Defect Onset after maternal antibodies diminish
Usually after 5-7 m/o, later childhood to adulthood
Bacteria: pneumococci, staphylococci, Hemophilus, campylobacter, mycoplasma
Virus: entovirus
Recurrent sinopulmonary infections, chronic GI symptoms, malabsorptions, arthritis, entroviral meningoencephalitis

16. X-linked agammaglobulinaemia(bruton)
In X-LA early maturation of B cells fails
Affect males
Few or no B cells in blood
Very small lymph nodes and tonsils
No Ig
Recurrent pyogenic infection

17. IgA deficiency Prevalence :1:700 , the most common PID
Serum IgA level < 10 mg/dl
Prevalence :1:700 , the most common PID
Most are asymptomatic , but have Increased rate of respiratory tract infection (R.T.I )
Some have recurrent G.I.T. , Urogenital tract Symptoms
Because of  lack of secretion of IgA on the mucous membrane of GIT and respiratory tract
Increased incidence of allergic and autoimmune diseases
Anti - convlusant drugs (phenytoin) may cause secondary deficiency

18. 2- IgA and IgG subclass defeciency
About 20% lack IgG2and IgG4
Susceptible to pyogenic infection
Result from failure in terminal differentiation of B cells

19. 3- Immunodfeiciency with increased IgM (HIgM)
Low or absent levels of IgA, IgG , IgE
Production of large amount of IgM >200mg/dl of polyclonal IgM
Susceptible to pyogenic infection
Due to inability of B cells to isotype switching
They have B cell

20. 4- Common Variable Immunodeficiency (CVID)
There are defect in T cell signaling to B cells
Acquired agammaglobulinemia in the 2nd or 3rd decade of life
Pyogenic infection
80% of patients have B cells that are not functioning
B cells are not defective but donot differentiate into immunoglobulin producing cell and fail to receive signaling from T lymphocytes
Risk of autoimmune disease and malignancy

21. 5- Hypogamaglobulinaemia of infancy
Due to delay in in IgG synthesis approximately up to 36 months
In normal infants synthesis begins at 3 months
Normal B lymphocytes
Probably lack help of T lymphocytes

22. Immunoglobulin Levels vs. Age
Immunoglobulin Levels vs. Age

23. Cellular Immunodeficiencies

24. Severe combined immunodeficiency (SCID)
Cellular deficiencies include:
Combined immunodeficiency (CID)
Severe combined immunodeficiency (SCID)
Ataxia-Telangiectasia syndrome (AT)
Wiskott-Aldrich syndrome (WAS)
DiGeorge syndrome
Chronic mucocutaneous candidiasis (CMCC)

25. DiGeorge's syndrome It the most understood T-cell immunodeficienc
Also known as congenital thymic aplasia/hypoplasia
Associated with hypoparathyroidism, congenital heart disease, fish shaped mouth.
Defects results from abnormal development of fetus during 6th-10th week of gestation when parathyroid, thymus, lips, ears and aortic arch are being formed

27. Combined T & B Immunodeficiencies

28. SEVERE COMBINED IMMUNODEFICENCY
In about 50% of SCID patients the immunodeficiency is x-linked whereas in the other half the deficiency is autosomal.
Early onset( 2-6 m/o)
Lymphopenia((< 2500 in infants)
They are both characterized by an absence of T cell and B cell immunity and absence (or very low numbers) of circulating T .
Very small thymus, no lymph node , no tonsil
Patients with SCID are susceptible to a variety of bacterial, viral, mycotic and protozoan infections.

29. The x-linked SCID is due to a defect in gamma-chain of IL-2 also shared by IL-4, -7, -11 and 15, all involved in lymphocyte proliferation and/or differentiation.
The autosomal SCIDs arise primarily from defects in adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) genes which results is accumulation of dATP or dGTP, respectively, and cause toxicity to lymphoid stem cells

30. Ataxia-telangiectasia
A complex of immunologic, neurologic, endocrinologic, hepatic and cutaneous abnormalities
ataxia(10-12y/o) ,telangiectasis (3-6 y/o)
Mutation in ATM gene
T-cells and their functions are reduced to various degrees.
B cell numbers are normal to low.
Low levels of IgA, IgE, high level of IgM
There is a high incidence of malignancy, particularly lymphoreicular & adenocarcinoma

32. Wiskott-Aldrich syndrome (immunodeficiency with thrombocytopenia and eczema)
X-linked xp
WASP ; assemby of actin filaments required for microvesicle formation downstream of protein kinase C and tyrosine kinase signaling
Low plaletlet, small size platelet
Associated with normal T cell numbers with reduced functions, which get progressively worse.

33. IgM concentrations are reduced but IgG levels are normal
Both IgA and IgE levels are elevated.
Boys with this syndrome develop severe eczema,bleeding tendency
They respond poorly to polysaccharide antigens and are prone to pyogenic infection.

34. Defects of the phagocytic system

35. Defects of phagocytic cells (numbers and/or functions) can lead to increased susceptibility to a variety of infections.
Bacteria,fungal infection
Skin and mucus membrane

36. Cyclic neutropenia Autosomal dominant
Mutation in ELA2(neutrophil elastase gene2)
It is marked by low numbers of circulating neutrophil approximately every three weeks. The neutropenia lasts about a week during which the patients are susceptible to infection. The defect appears to be due to poor regulation of neutrophil production.
Tx: r-GCSF ( granulocyte stimulating factor)

37. Severe congenital Neutropenia (Kostman)
Arrest in promyelocyte stage
Neutrophil count< 200
Mutation ELA2 or HAX1, autosomal recessive or dominant
Severe infections
20% prone to AML
Tx: r-GCSF

38. Shwachman Diamond Syndrome
Mutation in SBDS gene
Diarrhea, FTT, malabsorption till 4 m/o
Eczema, recurrent infections
Neutrophil count< 1000, pancytopenia
Risk of AML

39. Chronic granulomatous disease (CGD)
Defect in intra cellular killing
Normal chemotaxis, ingestion
Normal neutrophil count
x-linked (65%)& autosomal recessive
CGD is characterized lymphadenopathy, hepato- splenomegaly and chronic draining lymph nodes.
In majority of patients with CGD, the deficiency is due to a defect in NADPH oxidase that participate in phagocytic respiratory burst.
Infection with catalase positive organism: e coli, staph areus , fungal , nocardia, serratia

40. Leukocyte Adhesion Deficiency LAD1, LAD2,LAD3
Autosomal recessive
Defect in chemotaxis
These molecules are involved in diapedesis and hence defective neutrophils cannot respond effectively to chemotactic signals. 
Neutrophilia >12,000 , with infection >100,000
Delayed umblical cord separation > 2 wk
They don't have sign of inflammation such as swelling, warmth or pus formation

41. Chediak-Higashi syndrome (granule sorting disorder)
Mutation in lyst gene
Giant granule in cytoplasm of neutrophils
Respiratory burst is normal.
Associated with NK cell defect, platelet and neurological disorders

42. Albinism(oculocutaneous)
Repeated infections
Mild bleeding tendency
Peripheral neuropathy
Prone to hemophagocytic syndrome

43. Disorders of complement system

44. Complement abnormalities also lead to increased susceptibility to infections.
There are genetic deficiencies of various components of complement system, which lead to increased infections.
The most serious among these is the C3 deficiency which may arise from low C3 synthesis or deficiency in factor I or factor H. 
Defect in classic pathway; AUTOIMMUNE DISEASE
Congenital deficiency of C5, 6, 7, 8: > 50% MENINGOCOCCAL or GONOCOCCAL INFECTION( neisseria)

45. Hyper IgE (Job) syndrome
Autosomal dominant
Symptoms/signs
Coarse facial features/skeletal abnormalities
Recurrent staph infections
Impetigo (resistant)
Pneumonia with pneumatocele formation
Elevated IgE, Eosinophilia, Eczema

47. PID - treatments Immunoglobulin replacement
Bone Marrow Transplantation
Gene-based therapies
Antimicrobial management and prophylaxis
Nutritional Support
Patient Support Groups