Humoral Immunodeficiencies

Shobhita KatiyarJULY 20, 2016

PID : distribution

Distribution of identified PIDs in ESID registry database

B cell development

Surface receptors on developing B cell

CD 19, CD21 and CD 81

Clinical cytometry society,2008

B cell development

J Clin Immunol 2015

B cell immunodeficiency: Warning signs

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

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

Agammaglobulinemias

Agammaglobulinemias

X Linked Agammaglobulinemia (XLA)

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

Epidemiology

IncidenceUnknown because general population screening for the disorder is not done (1/3 new mutation)

Prevalence1/10,000 in the general population

Variable (1/379,000 in USA, 1/100,000 in Norway)

Clinical and Molecular Allergy ,2008

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 2005Cell 1993

Btk in B cell signaling

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

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

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

Btk expression in hematopoietic cells

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.

Clinical Manifestations

The Indian Journal of Pediatrics,2016

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)

Flowcytometry

Btk expression in monocytes

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

Blood, 2004

Common variable immunodeficiency

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

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

CVID: Diagnostic Criteria

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

CVID: genetic defects

Arthritis Research & Therapy 2012

British journal of Hematology,2009

Clinical manifestations

Blood,2008

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

• 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?

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

Selective IgA deficiency

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

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

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

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

Lancet, 1985

Clinical Manifestations Wide spectrum of manifestations:

Most patients asymptomatic → 90-95%

Symptomatic patients: Mucosal infections (RS & GI) Reccurrent sinopulmonary infections

Haemophilus influenzaeStreptococcus pneumoniae

Gastrointestinal infections/disordersGiardia lambliaMalabsorptionCeliac diseaseUlcerative colitisNodular lymphoid hyperplasia

Allergic disorder

Autoimmune conditions (Commonest after infections)Idiopathic thrombocytopenic purpuraHemolytic anemiaJuvenile rheumatoid arthritisThyroiditisSystemic lupus erthematosus

Malignancies

Clinical Manifestations

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.

Take Home Message

• Humoral immunodeficiencies : commonest PIDsExclude 2o causes of Ab deficiency

• Clinical features:Symptomatic after 1 year of ageEncapsulated bacterial infections (Resp. & GI)

• Improving prognosis:Suspect PID!!Timely treatment and prophylaxis of infections