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Predominantly antibody deficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Preeti Singh, M.B.B.S.[2], Ali Akram, M.B.B.S.[3], Anmol Pitliya, M.B.B.S. M.D.[4]

Overview

Overview

Predominantly antibody deficiencies (PAD) are the most common type of primary immunodeficiency diseases (PID). PAD is a large group of diseases which may vary widely from having a complete absence of B cells and decrease in all immunoglobulins to having deficiency in specific immunoglobulins. Depending on the phenotype, agammaglobulinemia or CVID, patients can present either in infancy or adulthood.The main clinical characteristic of patients with PAD is recurrent bacterial infections, low levels of immunoglobulin (ranging from agammaglobulinemia to hypogammaglobulinemia), and impaired response to vaccines and antigens. Treatment is by intravenous or subcutaneous immunoglobulins and treatment of infections by antibiotics.

Classification

Classification

 
 
Predominantly antibody deficiencies
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypogammaglobulinemia
 
Other antibody deficiencies


Hypogammaglobulinemia


 
 
 
 
Predominantly antibody deficiencies
(A): Hypogammaglobulinemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum immunoglobulin assays : IgG, IgA, IgM, IgE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IgG, IgA, and/or IgM ↓↓
→ B Lymphocyte (CD19+) enumeration (CMF)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B absent
 
 
 
B >1%
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-Linked Agammaglobulinemia
 
Common Variable Immunodeficiency Phenotype
 
 
 
CD19 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
µ heavy chain Def
 
 
 
CVID with no gene defect specified
 
 
CD20 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Igα def
 
 
 
PIK3CD mutation(GOF),PIK3R1 deficiency(LOF)
 
 
CD21 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Igβ def
 
 
 
PTEN deficiency(LOF)
 
 
TRNT1 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BLNK def
 
 
 
CD81 deficiency
 
 
NFKB1 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
λ5 def
 
 
 
TACI deficiency
 
 
NFKB2 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PI3KR1 def
 
 
 
BAFF receptor deficiency
 
 
IKAROS deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E47 transcription factor def
 
 
 
TWEAK deficiency
 
 
ATP6AP1 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mannosyl-oligosaccharide glucosidase deficiency (MOGS)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TTC37 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRF2BP2 deficiency
 
 
 
 
 
 

Other Antibody deficiencies

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Predominantly antibody deficiencies
(B): Other antibody deficiencies
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Immunolobulin Assays: IgG, IgA, IgM, IgE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Reduction in Serum IgG and IgA with NI/elevated IgM and Normal Numbers of B cells: Hyper IgM Syndromes
 
 
 
 
Isotype, Light Chain, or Functional Deficiencies with Generally NI Numbers of B cells
 
 
 
High B cell numbers due to constitutive NF-kB activation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AID deficiency
 
 
 
 
 
Selective IgA deficiency
 
 
 
 
CARD11 Gain of Function
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UNG deficiency
 
 
 
 
 
Transient hypogammaglobuliemia of infancy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INO80
 
 
 
 
 
IgG subclass deficiency with IgA deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MSH6
 
 
 
 
 
Isolated IgG subclass deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specific antibody deficiency with normal Ig levels and normal B cells
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ig heavy chain muations and deletions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kappa chain deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Selective IgM deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-linked Agammaglobulinemia

X-linked Agammaglobulinemia

  • It is an X linked disease, first described by Bruton in 1952.
  • It is caused by the mutation of BTK gene (present on the long arm of X chromosome) which encodes for the protein Bruton tyrosine kinase,which is associated with the maturation and differentiation of the pre B cell.[1]
  • The disruption of this protein can lead to significant decrease in all antibody isotypes, due to failure of Ig heavy chain rearrangement.[2]
  • Affected individuals generally present between 3 months to 3 years of age, with almost 90% becoming symptomatic by 5 years of age.[3]
  • Presence of maternal immunoglobulins provide transient protection, concealing symptoms of the disease and preventing early detection.
  • Physical examination typically shows absence of lymph nodes.
  • Patients are susceptible to recurrent infections with encapsulated organisms and enteroviruses, primarily effecting respiratory and gastrointestinal tracts.
  • Laboratory findings show defect in humoral immunity with absence or negligible amount of IgM, IgG, and IgA, as well as <2% of B cells lymphocytes. Neutropenia can also be seen.[4][1][5]
  • Treatment is mainly via hematopoietic stem cell therapy and through replacement of immunoglobulins either by intravenous or subcutaneous routes. Recurrent infections are prevented and treated by antibiotics.[6]

For more information on X-linked agammaglobulinemia, click here.

µ Heavy Chain Deficiency

µ Heavy Chain Deficiency

Igα Deficiency

Igα Deficiency

Igβ Deficiency

Igβ Deficiency

BLNK Deficiency

BLNK Deficiency

λ5 Deficiency

λ5 Deficiency

PI3KR1 Deficiency

PI3KR1 Deficiency

E47 transcription factor Deficiency

E47 transcription factor Deficiency

CVID With No Gene Specified

CVID With No Gene Specified

  1. Hypogammaglobulinaemia with IgG levels two standard deviations below the mean.
  2. Impaired vaccine responses or absent isohemagglutinins.
  3. Exclusion of other causes of hypogammaglobulinaemia.
  • Patients are susceptible to recurrent infections, autoimmunity and malignancy.
  • Treatment is by intravenous or subcutaneous replacement of immunoglobulins.[20]
PIK3CD mutation,PIK3R1 deficiency

PIK3CD mutation,PIK3R1 deficiency

  • Also known as activated phosphoinositide 3-kinase δ syndrome (APDS).
  • Autosomal dominant gain of function (GOF) mutation of PIK3CD gene, which encodes for P110δ subunit of phosphoinositide 3-kinase (PI3K) and loss of function (LOF) mutation of PIK3R1 gene, which encodes the p85α subunit of PI3K.
  • Mutations in PIK3CD gene leads to clinical features similar to mutation in PIK3R1 gene.[21]
  • Patients with mutations of gene for PIK3R1 show characteristics similar to that of patients carrying gain-of-function mutations of PIK3CD gene.
  • Mutations lead to hyperactive PI3K/AKT/mTOR signaling.[15][22]
  • Disease is characterized by low numbers of naive T cells, but a larger number of senescent effector T cells.
  • Patients present with upper and lower respiratory tract infections, lymphadenopathy, nodular lymphoid hyperplasia, early-onset autoimmunity, malignancies and recurrent viral infections with cytomegalovirus (CMV) and Epstein Barr virus (EBV).[23]
  • Treatment is via sirolimus and selective PI3Kδ inhibitors, intavenous and subcutaneous immunoglobulin replacement, prophylactic antibiotic, and hematopoietic stem cell transplant.[24]
PTEN deficiency

PTEN deficiency

CD 81 Deficiency

CD 81 Deficiency

TACI Deficiency

TACI Deficiency

  • Transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) is a part of tumor necrosis factor family and involved in B cell class switching.
  • Missense mutation of one allele of TNFRSF13B gene encoding for TACI leads to CVID like immunodeficiency.[28]
  • Patients present with increased susceptibility to encapsulated organisms, autoimmunity, and hypogammaglobulinemia.[29][30]
  • Treatment is by intravenous or subcutaneous replacement of immunoglobulins.[20]
BAFF Receptor Deficiency

BAFF Receptor Deficiency

  • Mutation of B-cell activating factor receptor (BAFF-R) prevents maturation of transitional B cell, leading to a CVID type adult onset immunodeficiency.
  • Incomplete maturation leads to hypogammaglobulinemia, but can in a few cases not manifest to clinical disease, with recurrent infections.
  • Patients show varying degrees immunodeficiency but normal IgA levels.[31][32]
  • Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.[20]
TWEAK Deficiency

TWEAK Deficiency

MOGS Deficiency

MOGS Deficiency

  • Mannosyl-oligosaccharide glucosidase (MOGS) deficiency causes a congenital disorder of glycosylation type IIb (CDG-IIb), also known as MOGS-CDG.
  • MOGS deficiency leads to improper processing of immunoglobulins, which shortens their half-life in circulation.
  • Few studies show that unlike most antibody deficiencies MOGS deficiency does not lead to clinical features of hypogammaglobulinemia like recurrent infections.
  • This is because cells with MOGS deficiency have altered glycosylation which prevents productive infection of multiple enveloped viruses.[34][35]
TTC37 Deficiency

TTC37 Deficiency

  • Tetratricopeptide Repeat Domain 37 (TTC37) deficency is an autosomal recessive disease causing syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) which has a similar immune phenotype to CVID.
  • TTC37 is involved in aberrant mRNAs decay.
  • Patient presents in infancy with low IgG and poor antigen-stimulation to vaccine.
  • Clinical features show infantile onset refractory diarrhea, hair and facial anomalies.[36][37]
  • Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.[20]
IRF2BP2 Deficiency

IRF2BP2 Deficiency

  • Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2) mutation leads to impaired differentiation of B cells.
  • Few studies show that most patients with this mutation are diagnosed with CVID in childhood.
  • Disease is characterized by recurrent infections,low levels of IgG, IgA and IgM , and decreased number of memory B cells. There is no T cell dysfunction.[38]
  • Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.[20]
CD19 Deficiency

CD19 Deficiency

CD20 Deficiency

CD20 Deficiency

CD21 Deficiency

CD21 Deficiency

TRNT1 Deficiency

TRNT1 Deficiency

NFKB1 Deficiency

NFKB1 Deficiency

NFKB2 Deficiency

NFKB2 Deficiency

IKAROS Deficiency

IKAROS Deficiency

  • IKAROS gene encodes for a family of hemopoietic-specific zinc finger proteins which are essential for lymphocyte development.[50]
  • Individuals show varied severity of clinical disease, despite most patients having low B cell and antibody count.
  • Deficiency leads to hypogammaglobulinemia, decreased response to vaccines, recurrent bacterial infections and malignancies.
  • Treatment is via replacement of immunoglobulins and treatment of infections with antibiotics.[51]
ATP6AP1 Deficiency

ATP6AP1 Deficiency

AID Deficiency

AID Deficiency

UNG deficiency

UNG deficiency

INO80

INO80

  • INO80 gene encodes for a subunit of the chromatin remodeling complex that is required for immunoglobulin class switching.
  • Patients have normal or elevated IgM levels, but low switched immunoglobulin isotypes (IgG, IgA, IgE).
  • Treatment is by replacement of immunoglobulins.[60]
MSH6

MSH6

  • MSH6 plays an important role in induction and repair of DNA double-strand breaks in immunoglobulin isotype switch regions, and is also involved in somatic hypermutation.[61]
Selective IgA Deficiency (SIgAD)

Selective IgA Deficiency (SIgAD)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Muhammad Affan M.D.[2]

Synonyms and keywords:: Selective IgA deficiency, SIgAD

Overview

Selective Immunoglobulin A deficiency (SIgAD) is the most common primary immunodeficiency and is defined as “serum level of IgA equal or below 7mg/dl in the presence of normal level of other immunoglobulins in individuals older than four years of age and in which other causes of hypogammaglobulinemia have been excluded”. The first cases with selective IgA deficiency were diagnosed in 1963-64, 10 years after immunoglobulin A was described in the serum by Graber and Williams. SIgAD is more prevalent in caucasians. It is classified based on either the laboratory values of B-cells subsets or the clinical phenotype of individuals with the condition. SIgAD has been attributed to an intrinsic B cell lymphocyte defect, T cell lymphocyte abnormalities and most recently an impairment in cytokine regulation indicating that it is a heterogenous dysfunction but the exact mechanism is still not clear. SIgAD may be genetically transferred but the inheritance pattern is variable. Several studies have reported SIgAD linkage with MHC and non MHC susceptibility genes that are also found in many autoimmune conditions which somewhat explains their association. Majority of patients with SIgAD are asymptomatic. Symptomatic patients may present with Infections such otitis media, sinopulmonary infections, gastrointestinal infections, allergies or autoimmune conditions. Diagnosis is usually based on serum level of immunoglobulin A. There is no specific treatment for selective IgA deficiency but there are several components of its management to prevent the progression and complications such as patient education, vaccination, use of antibiotics and immunoglobulins. The prognosis is generally very good but few cases may progress to common variable immunodeficiency that doesn’t predict a favorable outcome.

Historical Perspective

  • Immunoglobulin A was first discovered in the serum by Graber and Williams in 1953.[1]
  • Within 10 years, the first cases with selective IgA deficiency were identified in healthy as well as in patients with ataxia telangiectasia.[2][3]

Classification

  • Selective IgA deficiency may be classified based on either the laboratory values of B-cells subsets or the clinical phenotype of individuals with the condition.

Classification Based on Memory B cell Population

SIgAD can be classified based on the laboratory values of the B-cell subsets such as naive, IgM memory, switched memory or IgM+CD21- B cells in patients as compared to healthy individuals.[4]

 
 
 
 
 
 
 
 
 
 
 
 
Percentage of switched Memory B cells (CD 19+, CD 21+, IgD-)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SIgAD1
Less than 0.4% of switched memory B cells (CD19+, CD21+, IgD-)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SIgAD2
Greater than 0.4% of switched memory B cells (CD19+, CD21+, IgD-)
 

Classification Based on the Clinical Presentation

  • Health related quality of life(HRQL) can be compromised by the severity of symptoms in patients with selective IgA deficiency. It is classified based on the clinical presentation of the patients suffering from it.[5][6][7][8][9][10][11][12][13][14][15]
Clinical Phenotypes Description
Asymptomatic
  • About 60% of the patients are asymptomatic
  • Care should be taken while transfusing blood or blood products in these patients.
  • Regular monitoring i.e every 4-6 months is required as the disease can progress.
  • Patient should be educated but no therapeutic intervention is required.
Minor Infections
  • About 12% of the patients have minor infections.
  • Infections are usually caused by viral or bacterial agents that normally resolves without any sequel but sometimes it severe infections can occur Investigations for secondary immune defects such as IgG2 subclass deficiency or mannan-binding lectin should be done to find out predisposing factors.
  • A notable decrease in both physical and mental component affecting quality of life ( QoL) is observed in patients with this phenotype.
Allergy
  • About 15% of the patients with SIgAD have allergic manifestations predominantly.
  • Mental component is affected compromising the quality of life (QoL)in patients of this group.
  • Allergic manifestations are more severe in patients with SIgAD as compared to patients with normal IgA levels so special consideration should be given to the prevention and treatment of these patients. Evaluations of serum IgE level, skin prick test and lung function test are suggested in these patients.
Autoimmune
Severe symptoms
  • A few percent of the patient with SIgAD develop both recurrent or severe infections and autoimmune disorders fall into severe symptoms phenotype.
  • Associaton with HLA haplotype( A1, B8, DR1) increases the risk to develop severe symptoms and progression to common variable Immunodeficiency (CVID).
  • Mortality rate for this group is twice as compared to the general population.
  • It is proposed that the patient with this phenotype and the family history of both SIgAD and CVID perform the basic clinical and immunologic evaluation and regular follow-up examinations.


Pathophysiology

Pathogenesis

  • Several studies were carried out to establish the mechanism involved in selective IgA immunodeficiency but the exact pathogensis is still not clear.
  • SIgAD has been attributed to an intrinsic B cell lymphocyte defect, T cell lymphocyte abnormalities and most recently an impairment in cytokines regulation indicating that it is a heterogenous dysfunction.[8][16][17]
  • The most common pathological process involved in patients with selective immunoglobulin A deficiency is a maturation defect in B cells to produce IgA.[18]
  • Normally, the surface immunoglobulins are acquired in a sequential manner in B- cell differentiation. The first surface immunoglobulin to appear on B cells is IgM, as the cells mature they acquire surface IgD and sometimes IgA or IgG. A fully differentiated B cell performs a specfic function which means it would bear a specfic surface immunoglobulin. It is found that Patients with sIgAD have B cells arrested at a stage where they co-express surface IgM, IgD as well as IgA and donot develop into IgA secreting plasma cells.[19].
  • The abnormality appears to involve stem cells as it can be passed on by bone marrow transplantation.[20]
  • Cytokine dysregulation such as lack of IL-4, IL-6, IL-7, IL-10, TGF-b and most recently IL-21 is suggested to play a role in SIgAD.[17][21]

Genetics

  • Several genetic mutations are associated with SIgAD which suggest its polygenic nature but whether and how they imply causation is yet to be established.
SIgAD association with MHC and Non MHC Genes
MHC Susceptibility genes Non MHC Susceptibility genes
  • MHC class III: C2, C4A, C4B and MSH5[29]
  • Mutation in tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) gene that encodes for tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) protein also known as “transmembrane activator and calcium-modulator and cyclophilin ligand interactor”(TACI), a molecule responsible for isotype switching in B-cells is also found in this condition.[30][31]

Associated Conditions

Diseases Description
Common Variable Immunodeficiency
  • Common genetic basis has been proposed for IgA deficiency and common variable immunodeficiency by their existence in the members of the same family and the underlying B cell defect.[32]
  • IgA deficiency may progress into combined variable immundeficinecy.[33]
Autoimmune Conditions
Ataxia Telangectasia [38][39]
Risk for Cancer
  • There is an increased risk of cancer specifically of the gastrointestinal tract in adults. Though children with IgA deficiency are not at increased risk for cancers.[40][41]

Causes

  • The cause of selective IgA deficiency has not been identified. To review risk factors for the development of this disease, click risk factors.

Differentiating IgA Deficiency from Other Diseases

Disorder Defect (Mechanism of Development) Characteristic Features Clinical Presentation Laboratory Findings
X-Linked (Bruton) Agammaglobulinemia
Selective IgA Deficiency
  • Serum IgA < 7 mg/dl
  • Normal IgG and IgM levels
Common Variable Immunodeficiency
  • Defective B cell differentiation
  • May be acquired in 20-30 years of age
Autosomal dominant hype IgE syndrome (Job’s Syndrome)
  • Distinctive coarse facies
  • Cold (non-inflammatory) Staphylococcal abscesses
  • Retained primary teeth
  • Eczema
Severe combined immunodeficiency (SCID)
Ataxia Telangiectasia
Hyper IgM Syndrome
Wiskott-Aldrich Syndrome
  • Malignancy: can cause the reduction in the immunoglobulin production.[89]
  • Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia.
  • Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency.[90]
  • Other causes of primary humoral immunodeficiencies.
  • Smoking: may cause IgG2 subclass deficiency.[91]
  • Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.

Epidemiology and Demographics

Incidence of selective IgA deficiency
in blood donors among different countries
Country Incidence per 100,000 person years
Czech Republic[93] 244
Australia[94] 226
Finland[95] 200
Iceland[96] 157
England[97] 114
Brazil[98] 104
Iran[99] 102
Japan[100] 5


Incidence of selective IgA deficiency in
children and young age group among different
countries
Country Incidence per 100,000 person years
Canada[101] 746
Spain[102] 613
Turkey[103] 578
Finland[104] 531
Nigeria[105] 520
China[106] 398
Sweden[8] 52
  • High prevalence rate of SIgAD was observed in first degree relatives of symptomatic SIgAD patient with consanguineous marriages.[107]

Risk Factors

  • Positive family history of IgA deficiency or common variable immunodeficiency.[108]
  • The familial inheritance pattern is variable.[109]
  • Moreover penetrance of IgAD in the offspring varies with the gender of the transmitting parent with affected mother being more likely to transfer the disease to her offspring.[110]

Screening

  • As high rate of familial inheritance is in families with SIgAD, screening in first-degree relatives of such patients may be performed.[111][112]

Natural History, Complications, and Prognosis

Natural History

  • Children ≤ 4 years of age may have transient IgA defiecncy and have a full recovery.[113]
  • Majority of the patients > 4 years of age with SIgAD remain asymptomatic. Some of them will develop minor infections, allergies, autoimmune conditions and very few cases will have severe symptoms or progress to CVID.[114]

Complications

Prognosis

  • Prognosis in patients with selective IgA deficiency depends on the clinical phenotype and is generally good as most of the patient are asymptomatic.
  • Sponatanous recovery has been seen in cases with partial IgA deficiency.[115]
  • In rare occasions, the disease may progress to common variable immunodeficiency which doesn’t predict a favourable outcome.[11][116]


Diagnostic Criteria

  • Selective IgA deficiency is a laboratory finding that may not be associated with significant clinical presentaion.
  • Mainly based on direct measurement of serum IgA levels.
  • Serum IgA levels ≤ 7 mg/dl in the presence of normal IgG and IgM in patients older than 4 years of age is diagnostic.[56]
  • It can be transient finding in children ≤4 years of age.[117]
  • There should be high suspicion of SIgAD in patients having blood transfusion reaction.
  • In addition SIgAD should always be considered as one of the differentials in patients suffering from recurrent infections.

Symptoms

Physical Examination

  • Patients with SIgAD usually appear normal but may have physical findings due to associated conditions.

Laboratory Findings

  • serum IgA ≤ 0.7 mg/dl with normal levels of IgM and IgG.

Electrocardiogram

There are no ECG findings associated with SIgAD.

X-ray

  • There are no x-ray findings associated with SIgAD.

Echocardiography or Ultrasound

CT scan

  • There are no CT scan findings associated with SIgAD.

MRI

Other Imaging Findings

  • No other imaging studies are used to diagnose SIgAD.


Treatment

  • There is no specific treatment for selective IgA deficiency. Individuals can be managed based on their symptoms as the presentation varies.

Medical Therapy

  • Antibiotics are used to treat bacterial infections in patients with SIgAD. Prophylactic antibiotics may be used for recurrent infections[118]
  • If prophylactic antibiotics fail, rarely, a trial of immunoglobulin replacement therapy with minimal component of IgA may be tried especially in patients with associated antibody or subclass deficiency, though its use in SIgAD is controversial as it can lead to anaphylactic reactions and serum immunoglobulins should always be checked before its administration.[119].[120][121][122].
  • If blood transfusion is required, IgA deficient or washed blood components should be used.[123][124]
  • Other treatment options depends on the associated conditions.

Primary Prevention

  • Selective IgA deficiency is inherited with a variable inheritance pattern. There are no established measures for the primary prevention.

Secondary and Tertiary Prevention

  • Effective measures for secondary and tertiary prevention of selective IgA deficiency include:
  • Patient Education
    • Patient with severe IgA deficiency may have anaphylactic reaction secondary to blood transfusion or its products. It is specifically seen in patients with undetectable serum IgA levels. These patients develop anti IgA antibodies so they should be advised to wear medical alert bracelet.[125][121][49]
    • IgA levels should be periodically monitored in asymptomatic patients.
  • Vaccination:
  • Use of antibiotics:
    • Prophylactic antibiotics can be given to patients with SIgAD to prevent infections and other complications.[126]

References

  1. ↑ GRABAR P, WILLIAMS CA (January 1953). “[Method permitting the combined study of the electrophoretic and the immunochemical properties of protein mixtures; application to blood serum]”. Biochim. Biophys. Acta (in Undetermined). 10 (1): 193–4. PMID 13041735.
  2. ↑ DUNN HG, MEUWISSEN H, LIVINGSTONE CS, PUMP KK (November 1964). “ATAXIA-TELANGIECTASIA”. Can Med Assoc J. 91: 1106–18. PMC 1928365. PMID 14229760.
  3. ↑ Crabbé PA, Heremans JF (April 1966). “Lack of gamma A-immunoglobulin in serum of patients with steatorrhoea”. Gut. 7 (2): 119–27. PMC 1552348. PMID 4160439.
  4. ↑ Aghamohammadi A, Abolhassani H, Biglari M, Abolmaali S, Moazzami K, Tabatabaeiyan M, Asgarian-Omran H, Parvaneh N, Mirahmadian M, Rezaei N (2011). “Analysis of switched memory B cells in patients with IgA deficiency”. Int. Arch. Allergy Immunol. 156 (4): 462–8. doi:10.1159/000323903. PMID 21832837.
  5. ↑ Jörgensen GH, Gardulf A, Sigurdsson MI, Arnlaugsson S, Hammarström L, Ludviksson BR (March 2014). “Health-related quality of life (HRQL) in immunodeficient adults with selective IgA deficiency compared with age- and gender-matched controls and identification of risk factors for poor HRQL”. Qual Life Res. 23 (2): 645–58. doi:10.1007/s11136-013-0491-9. PMID 24022790.
  6. ↑ Yazdani R, Latif A, Tabassomi F, Abolhassani H, Azizi G, Rezaei N, Aghamohammadi A (2015). “Clinical phenotype classification for selective immunoglobulin A deficiency”. Expert Rev Clin Immunol. 11 (11): 1245–54. doi:10.1586/1744666X.2015.1081565. PMID 26306496.
  7. ↑ Hauge SC, Jensen CK, Nielsen LK, Pedersen OB, Sørensen E, Thørner LW, Hjalgrim H, Erikstrup C, Nielsen KR, Kaspersen KA, Didriksen M, Dziegiel M, Ullum H (March 2018). “The association of IgA deficiency on infection rate, self-perceived health, and levels of C-reactive protein in healthy blood donors”. APMIS. 126 (3): 248–256. doi:10.1111/apm.12807. PMID 29484746.
  8. ↑ 8.0 8.1 8.2 8.3 Cunningham-Rundles C (September 2001). “Physiology of IgA and IgA deficiency”. J. Clin. Immunol. 21 (5): 303–9. PMID 11720003.
  9. ↑ Jörgensen GH, Gardulf A, Sigurdsson MI, Arnlaugsson S, Hammarström L, Ludviksson BR (March 2014). “Health-related quality of life (HRQL) in immunodeficient adults with selective IgA deficiency compared with age- and gender-matched controls and identification of risk factors for poor HRQL”. Qual Life Res. 23 (2): 645–58. doi:10.1007/s11136-013-0491-9. PMID 24022790.
  10. ↑ Latiff AH, Kerr MA (March 2007). “The clinical significance of immunoglobulin A deficiency”. Ann. Clin. Biochem. 44 (Pt 2): 131–9. doi:10.1258/000456307780117993. PMID 17362578.
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  99. ↑ Rezvan H, Ahmadi D, Esmailzadeh S, Dayhimi I (April 2009). “Selective deficiency of immunoglobulin A among healthy voluntary blood donors in Iran”. Blood Transfus. 7 (2): 152–4. doi:10.2450/2008.0047-08. PMC 2689070. PMID 19503637.
  100. ↑ Kanoh T, Mizumoto T, Yasuda N, Koya M, Ohno Y, Uchino H, Yoshimura K, Ohkubo Y, Yamaguchi H (1986). “Selective IgA deficiency in Japanese blood donors: frequency and statistical analysis”. Vox Sang. 50 (2): 81–6. PMID 3485858.
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  102. ↑ Pereira LF, Sapiña AM, Arroyo J, Viñuelas J, Bardají RM, Prieto L (July 1997). “Prevalence of selective IgA deficiency in Spain: more than we thought”. Blood. 90 (2): 893. PMID 9226194.
  103. ↑ Baştürk B, Sari S, Aral A, Dalgiç B (2011). “Prevalence of selective immunoglobulin A deficiency in healthy Turkish school children”. Turk. J. Pediatr. 53 (4): 364–8. PMID 21980837.
  104. ↑ Savilahti E, Pelkonen P, Visakorpi JK (October 1971). “IgA deficiency in children. A clinical study with special reference to intestinal findings”. Arch. Dis. Child. 46 (249): 665–70. PMC 1647824. PMID 5118054.
  105. ↑ Ezeoke AC (March 1988). “Selective IgA deficiency (SIgAD) in Eastern Nigeria”. Afr J Med Med Sci. 17 (1): 17–21. PMID 2834928.
  106. ↑ Feng L (February 1992). “[Epidemiological study of selective IgA deficiency among 6 nationalities in China]”. Zhonghua Yi Xue Za Zhi (in Chinese). 72 (2): 88–90, 128. PMID 1327440.
  107. ↑ Rezaei N, Abolhassani H, Kasraian A, Mohammadinejad P, Sadeghi B, Aghamohammadi A (August 2013). “Family study of pediatric patients with primary antibody deficiencies”. Iran J Allergy Asthma Immunol. 12 (4): 377–82. PMID 23996714.
  108. ↑ Vorechovský I, Zetterquist H, Paganelli R, Koskinen S, Webster AD, Björkander J, Smith CI, Hammarström L (November 1995). “Family and linkage study of selective IgA deficiency and common variable immunodeficiency”. Clin. Immunol. Immunopathol. 77 (2): 185–92. PMID 7586726.
  109. ↑ Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Crow YJ, Cunningham-Rundles C, Etzioni A, Franco JL, Holland SM, Klein C, Morio T, Ochs HD, Oksenhendler E, Puck J, Tang M, Tangye SG, Torgerson TR, Sullivan KE (January 2018). “International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity”. J. Clin. Immunol. 38 (1): 96–128. doi:10.1007/s10875-017-0464-9. PMC 5742601. PMID 29226302. Vancouver style error: initials (help)
  110. ↑ Vorechovský I, Webster AD, Plebani A, Hammarström L (April 1999). “Genetic linkage of IgA deficiency to the major histocompatibility complex: evidence for allele segregation distortion, parent-of-origin penetrance differences, and the role of anti-IgA antibodies in disease predisposition”. Am. J. Hum. Genet. 64 (4): 1096–109. PMC 1377834. PMID 10090895.
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  115. ↑ Plebani A, Ugazio AG, Monafo V, Burgio GR (April 1986). “Clinical heterogeneity and reversibility of selective immunoglobulin A deficiency in 80 children”. Lancet. 1 (8485): 829–31. PMID 2870316.
  116. ↑ Litzman J, Burianova M, Thon V, Lokaj J (1996). “Progression of selective IgA deficiency to common variable immunodeficiency in a 16 year old boy”. Allergol Immunopathol (Madr). 24 (4): 174–6. PMID 8939274.
  117. ↑ Ostergaard PA (June 1980). “Clinical and immunological features of transient IgA deficiency in children”. Clin. Exp. Immunol. 40 (3): 561–5. PMC 1538944. PMID 7418266.
  118. ↑ Gustafson R, Gardulf A, Granert C, Hansen S, Hammarström L (September 1997). “Prophylactic therapy for selective IgA deficiency”. Lancet. 350 (9081): 865. doi:10.1016/S0140-6736(05)62034-X. PMID 9310611.
  119. ↑ Bonilla FA, Bernstein IL, Khan DA, Ballas ZK, Chinen J, Frank MM, Kobrynski LJ, Levinson AI, Mazer B, Nelson RP, Orange JS, Routes JM, Shearer WT, Sorensen RU (May 2005). “Practice parameter for the diagnosis and management of primary immunodeficiency”. Ann. Allergy Asthma Immunol. 94 (5 Suppl 1): S1–63. PMID 15945566.
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  124. ↑ Vassallo RR (2004). “Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products”. Immunohematology. 20 (4): 226–33. PMID 15679454.
  125. ↑ Horn J, Thon V, Bartonkova D, Salzer U, Warnatz K, Schlesier M, Peter HH, Grimbacher B (February 2007). “Anti-IgA antibodies in common variable immunodeficiency (CVID): diagnostic workup and therapeutic strategy”. Clin. Immunol. 122 (2): 156–62. doi:10.1016/j.clim.2006.10.002. PMID 17137841.
  126. ↑ Freeman AF, Holland SM (December 2009). “Antimicrobial prophylaxis for primary immunodeficiencies”. Curr Opin Allergy Clin Immunol. 9 (6): 525–30. doi:10.1097/ACI.0b013e328332be33. PMID 19812481.


Template:WikiDoc Sources

Kappa chain Deficiency

Kappa chain Deficiency

Selective IgM Deficiency

Selective IgM Deficiency

CARD11 Gain of Function

CARD11 Gain of Function

References

References

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  2. ↑ Rawlings DJ, Witte ON (April 1994). “Bruton’s tyrosine kinase is a key regulator in B-cell development”. Immunol. Rev. 138: 105–19. PMID 8070812.
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  4. ↑ Fried AJ, Bonilla FA (July 2009). “Pathogenesis, diagnosis, and management of primary antibody deficiencies and infections”. Clin. Microbiol. Rev. 22 (3): 396–414. doi:10.1128/CMR.00001-09. PMC 2708392. PMID 19597006.
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  7. ↑ Yel L, Minegishi Y, Coustan-Smith E, Buckley RH, Trübel H, Pachman LM, Kitchingman GR, Campana D, Rohrer J, Conley ME (November 1996). “Mutations in the mu heavy-chain gene in patients with agammaglobulinemia”. N. Engl. J. Med. 335 (20): 1486–93. doi:10.1056/NEJM199611143352003. PMID 8890099.
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