This document discusses several primary immunodeficiencies including agammaglobulinemia, common variable immunodeficiency, and selective IgA deficiency. It provides information on the epidemiology, pathophysiology, clinical manifestations, diagnosis, and treatment of each condition. Key points include that agammaglobulinemia is caused by mutations in the BTK gene that halt B cell development, common variable immunodeficiency has unknown causes in most cases, and selective IgA deficiency involves a block in differentiation of B cells into IgA secreting plasma cells. Clinical features often involve recurrent respiratory and gastrointestinal infections. Treatment focuses on antibody replacement and infection prevention.

1. Shobhita Katiyar
JULY 20, 2016

2. PID : distribution
Distribution of identified PIDs in ESID registry database

3. B cell development

4. Surface receptors on developing B cell

5. CD 19, CD21 and CD 81

6. Clinical cytometry society,2008
B cell development

7. J Clin Immunol 2015

8. B cell immunodeficiency: Warning signs

9. Question: Which is the most common antibody
produced in the body?
• IgG
• IgM
• IgA
• IgE
• IgD

10. Question: Which is the most common antibody
in circulation in the body?
• IgG
• IgM
• IgA
• IgE
• IgD

11. Agammaglobulinemias

12. Agammaglobulinemias

14.  First recognized human immune deficiency
 Discovered in 1952 by Colonel Ogden Bruton
 Case report : 8-year-old boy, recurrent infections over a 4-year period
- Majority of infections: pneumococcus
- Bruton attempted to vaccinate → no γ globulin was production
- Treated with monthly intramuscular injections of human γ globulin
with significant clinical improvement
- No family history
 Subsequent cases revealed a similar clinical phenotype with an X-
linked pedigree
Agammaglobulinemia.Pediatrics,1952, Clin Exp Immunol,2000.
Introduction

15. Epidemiology
 Incidence
Unknown because general population screening for the disorder is not done
(1/3 new mutation)
 Prevalence
1/10,000 in the general population
Variable (1/379,000 in USA, 1/100,000 in Norway)
Clinical and Molecular Allergy ,2008

16. Pathophysiology
 Cause : mutations in the human BTK gene – halts B cell development
 In 1993, two groups of investigators independently/simultaneously
discovered mutated gene in XLA.
European group called atk gene→ ammaglobulinemia tyrosine kinase
American group called bpk gene → B-cell pro-genitor kinase
 A compromise was reached with the term;
‘Btk (Bruton's tyrosine kinase)’ in honor of Dr. Bruton
Immunological Reviews 2005
Cell 1993

17. Btk in B cell signaling

18. Btk gene & protein
 Contains 19 exons → 37 kb of DNA
 Intracellular signal transduction molecule
- Member of Tec family ; 75 kDa cytoplasmic tyrosine kinase
National Library of Medicine,2012

19.  BTK protein consists of 5 functional domains
- Pleckstrin Homology (PH) domain
- Tec homology (TH) domain
- Src homology 3 (SH3) domain
- Src homology 2 (SH2) domain
- Catalytic kinase (SH1) domain
 Mutations in all domains of the BTK gene have been shown to cause
XLA.
protein-protein interactions
Catalytic activity
Journal of Hematology and Oncology, 2013

20. Question: Which cell population will you gate for
analyzing Btk expression in a suspected patient?

21. Btk expression in hematopoietic cells

22. Btk Mutation
 >600 different mutations in the BTK gene have been found
 90% : Single base pair substitution & insertion or deletion < 5 bp
 No clear correlation has been found between mutation location and
clinical phenotype.
 55% of males have no family history of XLA
- De novo causing mutation : 15%-20%
- Mother is a carrier of a disease-causing mutation : 80%-85%
 Female carriers of XLA can be identified by the presence of either;
- non-random X chromosome inactivation in their B cells or
- mutated gene (if known in the family)
National Library of Medicine,2012.

23. Clinical Manifestations
The Indian Journal of Pediatrics,2016

24. Diagnosis
 Family history
 Clinical manifestations
 Intermittent neutropenia can occur at the onset of an acute infection
 Low serum IgG, IgM and IgA level
 Peripheral blood CD19 B-cell counts < 2%
 Laboratory investigation by
 Prenatal diagnosis: detection of the mutated gene in chorionic villus
or amniocentesis samples
 Confirmation by demonstrating;
- absence of BTK protein in monocytes (flowcytometry)
- detection of a mutation in BTK in DNA (sequence analysis)

25. Flowcytometry
Btk expression in monocytes

26. Treatment
 Early diagnosis and treatment would improve the survival
 Intravenous immunoglobulin (IVIG) and antibiotic prophylaxis are
conventional treatments → increased survival rate
 Genetic counselling, carrier detection, and prenatal diagnosis
 Gene therapy

27. Blood, 2004

29. CVID
 Term coined in 1971 by WHO committee to separate less well
defined antibody deficiency syndrome from others
 Causes of CVID: largely obscure; no universally accepted definition
• A group of antibody deficiencies that lack a more specific genetic or
phenotypic classification
• Patients with antibody deficiency (no secondary causes for it)
lacking uniform genetic defect and clinical features

30. Epidemiology
 Prevalence 1 in 25,000 to 1 in 50,000
 Most patients are diagnosed between the ages of 20 and 40 years,
approximately 20% are under the age of 20
 Affects both sexes equally, boys > girls in children
Blood,2012

31. CVID: Diagnostic Criteria

35. Genetics
 90% sporadic cases – unknown defect
 10% Familial
- AD with variable penetrance(80%)
- AR (20%)

36. CVID: genetic defects
Arthritis Research & Therapy 2012

37. British journal of Hematology,2009
Clinical manifestations

38. Blood,2008

39. Autoimmunity in CVID
 Others include
 Neutropenia
 Pernicious anaemia
 Anticardiolipin Ab
 Antiphospholipid syndrome
 Diabetes mellitus
 Juvenile Idiopathic Arthritis
 Uveitis
 Multiple sclerosis
 Systemic lupus erythematosus
 Autoimmune thyroid disease
 Lichen planus
 Vasculitis
 Vililago
American Society of Hematology,2012

40. • Q: An 8 year old boy p/w lower limb predominant arthritis of 4
m duration. It was not controlled with NSAIDs alone and was
started on SSZ f/b Mtx in combination for it.
• Again, there was incomplete response and he also developed
bloody diarrhoea 2 months later. He was investigated for
possible PID with autoimmunity. No family history.
• Hb = 8gm%, TLC = 14000, N90 L6, Plt = 3.3 Lac
• STP = 5.6 gm, Alb. = 3.2 gm,  IgG, A and M
• Imp: Panhypogamamglobulinemia
• Diagnosis & next step?

41. Treatment
 Primary treatment is antibody replacement: IVIG or SCIG
 IVIG: 400 – 600 mg/Kg q3-4 weeks
 SCIG: 100 – 150 mg/Kg/week
 Ch. Lung Disease and IBD: Higher doses
 Trough levels: 7gm/L
 Infection prevention: Antibiotic prophylaxis
 Autoimmune phenomena: Steroids, IS, Rtx
 Severe hematological changes (chronic transfusion need, leukopenia,
Thrombocytopenia) & secondary malignancies - Stem cell transplantation

43. Introduction
 IgA: first described in serum in 1953; Selective IgA deficiency: first reported
in 1964
 Incidence – Caucacians > Asians
 No well defined genetic susceptibility → AD, AR and sporadic
 Most abundant Ab isotype produced in body
 Subclasses: IgA 1 and IgA 2 → locus α1 and α2 on chromosome 14
 Circulating IgA : monomeric
- predominantly IgA 1
- Produced in BM from plasma cell
 Secretory IgA : dimeric
- predominantly IgA 2
- Produced locally in the mucosal tissue

44. Definition
Selective IgA Deficiency
 Male / Female > 4 yrs. of age
 Serum IgA < 7 mg/dL
 Normal serum IgG and IgM
 Other causes of hypogammaglobulinemia have been excluded
 Normal IgG antibody response response to vaccination
Partial IgA Deficiency
 Serum IgA > 7 mg/dL but 2 SD below for normal of that age

45. Ig A
 Most abundant Ab isotype produced in body
 Subclasses: IgA 1 and IgA 2 → locus α1 and α2 on chromosome 14
 Exists in monomeric and dimeric forms
 Circulating IgA : monomeric
- predominantly IgA 1
- Produced in BM from plasma cell
 Secretory IgA : dimeric
- predominantly IgA 2
- Produced locally in the mucosal tissue

46. Pathogenesis
 Primary defect: block in differentiation of B cells → IgA secreting
plasma cell (? At the level of stem cells)
 α heavy chain deletions: chromosome 14
 Abnormalities in cytokine network: IL-4,6,7,10,21 and TGF-β
 Mutations reported : TACI, APRIL,TNFRSF13B
 Disease association with MHC haplotype 8.1(HLA A1,B8,DR3 and
DQ2) → ↑ risk of developing disease

47. Lancet, 1985

48. Clinical Manifestations
 Wide spectrum of manifestations:
 Most patients asymptomatic → 90-95%
 Symptomatic patients: Mucosal infections (RS & GI)
 Reccurrent sinopulmonary infections
Haemophilus influenzae
Streptococcus pneumoniae
 Gastrointestinal infections/disorders
Giardia lamblia
Malabsorption
Celiac disease
Ulcerative colitis
Nodular lymphoid hyperplasia

49.  Allergic disorder
 Autoimmune conditions (Commonest after infections)
Idiopathic thrombocytopenic purpura
Hemolytic anemia
Juvenile rheumatoid arthritis
Thyroiditis
Systemic lupus erthematosus
 Malignancies
Clinical Manifestations

50. Treatment
 Asymptomatic patients: none
 Mainstay treatment : treatment of associated diseases
 IgG subclass deficiency/antibody deficiency → IVIG,SCIG with
product containing minimal IgA
 Prevent anaphylactic reaction secondary to blood transfusion
 Recurrent respiratory infections : antibiotics
 Observation: Patients may progress to develop CVID.

51. Take Home Message
• Humoral immunodeficiencies : commonest PIDs
Exclude 2o causes of Ab deficiency
• Clinical features:
Symptomatic after 1 year of age
Encapsulated bacterial infections (Resp. & GI)
• Improving prognosis:
Suspect PID!!
Timely treatment and prophylaxis of infections