Predominantly antibody deficiency

# 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

## Hypogammaglobulinemia

### Other Antibody deficiencies

# 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.
- The disruption of this protein can lead to significant decrease in all antibody isotypes, due to failure of Ig heavy chain rearrangement.
- Affected individuals generally present between 3 months to 3 years of age, with almost 90% becoming symptomatic by 5 years of age.
- 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.
- 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.
For more information on X-linked agammaglobulinemia, click here.

#  Heavy Chain Deficiency
-  heavy chain deficiency has Autosomal recessive (AR) transmission.
- It is caused by mutation of  heavy chain (IGHM) on chromosome 14.
- This mutation is phenotypically similar to X-linked agammaglobulinemia, but unlike X-linked agammaglobulinemia can also be seen in females, yet there has been a study that provides data showing clinically significant difference between the two.
- Treatment is mainly via replacement of immunoglobulins by intravenous or subcutaneous routes, hematopoietic stem cell therapy and use of prophylactic and curative antibiotics.

# Ig Deficiency
- Ig Deficiency has autosomal recessive (AR) transmission.
- Mutation of Ig(CD79) a component of B cell receptor (BCR). Mutations in pre-BCR complex many times lead to truncation of B cell development.
- It causes a B cell defect which leads to a clinical picture similar to X-linked agammaglobulinemia.
- Patients have increased susceptibility to bacterial infections and otitis media.
- Diagnosis is mainly by polymerase chain reaction (PCR) or single strand conformational polymosrphism analysis(SSCA).
- Treatment is mainly through replacement of immunoglobulins by intravenous or subcutaneous routes, hematopoietic stem cell therapy and use of prophylactic and curative antibiotics..

# Ig Deficiency
- Ig deficiency has autosomal recessive (AR) transmission.
- Caused by mutation in the CD79B gene on chromosome 17.
- Ig is a signal transduction molecule similar to Ig and is essential for B cell receptor(BCR) expression.
- Patients generally present with reduced immunoglobulins which leads to frequent bacterial infections of upper and lower respiratory tract similar to other agammaglobulinemia like X-linked agammaglobulinemia.
- Treatment is mainly via replacement of immunoglobulins by intravenous or subcutaneous route,  hematopoietic stem cell therapy and use of prophylactic and curative antibiotics.

# BLNK Deficiency
- BLNK deficiency has autosomal recessive (AR) transmission.
- BLNK gene on chromosome 10 encodes for a scaffold molecule B cell linker protein (BLNK, SLC-65) and is crucial for the development of pre B cell.
- Patients generally present with recurrent bacterial infections, otitis media and upper and lower respiratory tract infections similar to X-linked agammaglobulinemia.
- Treatment is mainly via replacement of immunoglobulins by intravenous or subcutaneous routes, hematopoietic stem cell therapy and use of prophylactic and curative antibiotics.

# 5 Deficiency
- 5 deficiency has autosomal recessive (AR) transmission..
- It is caused by mutation of 5 (IGLL1), component of B cell receptor, on chromosome 22.
- Leads to clinical features similar to X-linked agammaglobulinemia.
- Treatment is mainly through replacement of immunoglobulins by intravenous or subcutaneous routes, hematopoietic stem cell therapy and use of prophylactic and curative antibiotics.

# PI3KR1 Deficiency
- PIK3R1 gene encodes for the p85 subunit of class IA phosphoinositide 3-kinases (PI3Ks).
- Patients present with history of recurrent bacterial infections and positive family history, similar to clinical features seen in X-linked agammaglobulinemia.
- Treatment is mainly through replacement of immunoglobulins by intravenous or subcutaneous routes, hematopoietic stem cell therapy and use of prophylactic and curative antibiotics.

# E47 transcription factor Deficiency
- Mutation of E47 transcription factor.
- This mutation leads to improper differentiation of B cell from lymphoid precursors.
- Patients present with few B cells characterized increased expression of CD19, but without B cell receptor (BCR).
- Treatment is mainly through replacement of immunoglobulins by intravenous or subcutaneous routes, hematopoietic stem cell therapy and use of prophylactic and curative antibiotics.

# CVID With No Gene Specified
- Common variable immune deficiency (CVID) is the most common primary immune deficiency presenting in adult patients.
- Patients show symptoms of disease later in life and the cause is mainly polygenic.
- CVID is a diagnosis of exclusion due to its varied etiology.
- The ESID/PAGID criteria is for diagnosis is:
- Hypogammaglobulinaemia with IgG levels two standard deviations below the mean.
- Impaired vaccine responses or absent isohemagglutinins.
- Exclusion of other causes of hypogammaglobulinaemia.
- Patients are susceptible to recurrent infections, autoimmunity and malignancy.
- Treatment is by intravenous or subcutaneous replacement of immunoglobulins.

# PIK3CD mutation,PIK3R1 deficiency
- Also known as activated phosphoinositide 3-kinase  syndrome (APDS).
- Autosomal dominant gain of function (GOF) mutation of PIK3CD gene, which encodes for P110 subunit of phosphoinositide 3-kinase (PI3K) and loss of function (LOF) mutation of PIK3R1 gene, which encodes the p85 subunit of PI3K.
- Mutations in PIK3CD gene leads to clinical features similar to  mutation in PIK3R1 gene.
- 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.
- 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).
- Treatment is via sirolimus and selective PI3K inhibitors, intavenous and subcutaneous immunoglobulin replacement,  prophylactic antibiotic, and hematopoietic stem cell transplant.

# PTEN deficiency
- Phosphatase and tensin homolog (PTEN) is an inhibitory component of phosphoinositide 3-kinase (PI3K) signalling network.
- Loss of function mutation of this gene leads to up regulation of PI3K/AKT/mTOR pathway leading to APDS like immunodeficiency.
- Immunodeficiency leads to recurrent infections, Cowden disease and malignancies.
- Treatment is by intravenous and subcutaneous immunoglobulin  and antibiotics.

# CD 81 Deficiency
- CD81 is a B cell surface protein (part of CD19 complex) which helps in antigen recognition.
- Deficiency is characterized by decreased in number of B cell, hypogammaglobulinemia , impaired antibody responses, and absence of CD19 expression on B cells.
- Patients present with recurrent  infections of upper and lower respiratory tract.
- Treatment is mainly through replacement of immunoglobulins by intravenous or subcutaneous routes, hematopoietic stem cell therapy and use of prophylactic and curative antibiotics.

# 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.
- Patients present with increased susceptibility to encapsulated organisms, autoimmunity, and hypogammaglobulinemia.
- Treatment is by intravenous or subcutaneous replacement of immunoglobulins.

# 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.
- Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.

# TWEAK Deficiency
- CVID like phenotype caused by, an autosomal dominant transmitted, deficiency in TNF-like weak inducer of apoptosis (TWEAK).
- Mutation in TWEAK is associated with regulation of BAFF associated B cell development leading to impaired B cell survival and isotype class switching.
- Disease is characterized by recurrent infection and impaired response to vaccination.
- Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.

# 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.

# 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.
- Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.

# 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.
- Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.

# CD19 Deficiency
- CD19 surface expression can be absent in cases of homozygous CD19 deficiency or CD81 deficiency.
- Deficiency leads to impaired formation of CD19 complex and  B cell development and antibody response.
- Patients show increased susceptibility to infection, hypogammaglobulinemia and impaired response to vaccines.
- Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.

# CD20 Deficiency
- CD20 is essential for T cell independent antibody response.
- Deficiency of CD20 therefore leads to reduced ability to mount an antibody response.
- Patients have increased risk of infections by encapsulated bacteria, hypogammaglobulinemia, due to decrease somatic hypermutation, and normal B cell numbers; but a decrease in number of circulating memory B cells.
- Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.

# CD21 Deficiency
- CD21 is a receptor for complement C3d which helps in antigen specific response.
- Patients present with increased susceptibility to infections, decreased immunoglobulin class switching, chronic diarrhea and hypogammaglobulinemia.
- Unlike patients with CD19 and CD20 deficiency patients with CD 21 have less sever clinical phenotype, and are able to mount specific antibody response to vaccines but not very well with polysaccharide vaccines.
- Treatment is by curative antibiotics to treat recurrent infections.

# TRNT1 Deficiency
- TRNT1 gene encodes for  CCA-adding transfer RNA nucleotidyl transferase (TRNT1) enzyme, an tRNA processing enzyme.
- It leads to a childhood syndromic form of congenital sideroblastic anemia (CSA) associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD).
- Disease is characterized by childhood developmental delay, neurodegeneration, seizures, sensorineural deafness, and other multi organ anomalies.
- Treatment is by intravenous immunoglobulin, transfusion for anemia and by bone marrow transplantation.

# NFKB1 Deficiency
- Nuclear factor B subunit 1 (NFKB1) plays an important role in B cell differentiation and function.
- NFKB1 is essential for immunoglobulin class switching and deficiency can lead to an hyper-IgM like syndrome with lower IgG and IgA production.
- Sporadic or familial loss of function mutations of NFKB1 leads to progressive humoral immunodeficiency, with a highly variable clinical spectrum.
- It is considered the most common known monogenic cause of CVID .
- Patients present with hypogammaglobulinemia, recurrent upper and lower respiratory tract infections, as well as non-infectious complications like lymphadenopathy, splenomegaly, autoimmunity and rarely malignancy.
- Individually usually require lifelong followup.
- Patients are treated with replacement immunoglobulins depending on severity of antibody deficiency.

# NFKB2 Deficiency
- Nuclear factor kappa-B subunit 2 (NFKB2) is a part of noncolonical NF-B pathway and is involved in B cell maturation and antibody development.
- Mutations leading to deficiency cause CVID with  early onset central adrenal insufficiency and at times ectodermal dysplasia.
- Patients presents with ACTH deficiency, recurrent infections, hypogammaglobulinemia, decreased response to vaccines and autoimmunity effecting the skin, hair, and nails
- Treatment is via immunoglobulin replacement therapy and glucocorticoid replacement.

# IKAROS Deficiency
- IKAROS gene encodes for a family of hemopoietic-specific zinc finger proteins which are essential for lymphocyte development.
- 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.

# ATP6AP1 Deficiency
- ATP6AP1 encodes for Ac45 of human V-ATPase and is homologus to yeast V-ATPase assembly factor Voa1.
- This gene is involved in B cell functioning, antigen recognition and antibody production.
- Deficiency therefore leads to hypogammaglobulinemia and increased susceptibility to infections.
- Deficiency leads to pathology in the liver (ranging from cirrhosis to end-stage liver failure), leukopenia , and low levels of copper and ceruloplasmin, and high alkaline phosphatase.
- Patients are treated with intravenous immunoglobulins.

# AID Deficiency
- Activation-induced cytidine deaminase (AID) is expressed by germinal center B cells and plays a crucial role in B cell terminal differentiation and antibody response (somatic hypermutation and class switching).
- Deficiency leads to a form of the hyper-IgM syndrome (HIGM2), which shows autosomal recessive inheritance.
- Disease is characterized by loss of immunoglobulin class switching and somatic hypermutation, as well as lymphoid hyperplasia with giant germinal centers and enlarged lymph nodes requiring frequent biopsies.
- Patients typically have normal or increased IgM, but lack IgG and IgA.
- Immunodeficiency is complicated by autoimmune disorders, gastric illnesses due to impaired IgA production, and recurrent bacterial infections of the upper respiratory system.
- Treatment is via replacement of immunoglobulins, corticosteroids for autoimmunity.

# UNG deficiency
- Uracil-N glycosylase (UNG) removes uracil in DNA plays a role in suppressing GC-to-AT transition mutations.
- UNG removes uracil residues leading to DNA breaks that helps initiate class switching.
- UNG deficiency has an autosomal recessive mutation, this leads to  an normal or increased serum IgM concentrations with low or absent serum IgG, IgA, and IgE concentrations.
- Disease is characterized by increased susceptibility to bacterial infections, lymphoid hyperplasia leading to enlarged lymph nodes.
- Treatment is by immunoglobulin replacement therapy and treatment of infections with antibiotics.

# 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.

# 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.

# Selective IgA Deficiency (SIgAD)
- Selective Immunoglobulin A (IgA) deficiency 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".
- Several genetic mutations are associated with SIgAD which suggest its polygenic nature but most commonly it is due to a maturation defect in B cells to produce IgA.
- B cells arrested at a stage where they coexpress surface IgM, IgD as well as IgA and donot develop into IgA secreting plasma cells..
- The abnormality appears to involve stem cells as it can be passed on by bone marrow transplantation.
- Majority of the individuals are asymptomatic, but may present with recurrent respiratory and gastrointestinal infections (mucosal infections), autoimmune diseases, atopy and anaphylaxis to IgA containing products.
- IgA levels should be periodically monitored in asymptomatic patients.
- There is no specific treatment for selective IgA deficiency. Individuals can be managed based on their symptoms as the presentation varies.
- Antibiotics are used to treat bacterial infections in patients with SIgAD.
- Prophylactic antibiotics can be used for recurrent infections.
- If prophylactic antibiotics fail, a trial of intravenous or subcutaneous immunoglobulin replacement therapy with minimal component of IgA may be tried.
- Serum IgA antibodies should always be checked in such patient before administration of IVIG to prevent the risk of anaphylaxis.
- If blood transfusion is required, IgA deficient or washed blood components should be used.
- Pneumococcal vaccine is recommended in patients with SIgAD to reduce the risk of sino-pulmonary infections.

# Kappa chain Deficiency
- Approximately 2/3 of the total immunoglobulins light chains, circulating and surface bound, are Kappa light chains.
- Deficiency is due to a genetic defect causing homozygous T to G substitution which leads to absent kappa light chain immunoglobulins, but the concentration of immunoglobulin isotypes (IgG, IgA, IgM, IgE and IgD) are normal due to compensation by lambda light chains.
- This leads to increased susceptibility bacterial infections of respiratory and gastrointestinal system, autoimmunity and IgA deficiency.
- Patients require frequent hospitalization and antibiotic therapy to treat recurrent infections.

# Selective IgM Deficiency
- Selective IgM deficiency (SIGMD) is defined as "serum IgM levels below two SD of mean with normal serum IgG IgA and T cells".
- Cause of IgM deficiency is due to many genetic defects, but commonly due to  22q11.2 chromosome deletion.
- Individuals with SIGMD present with increased susceptibility to infections by microorganisms and protozoa, atopy, impaired antibody response and autoimmune diseases.
- Treatment is via immunoglobulin replacement and treatment of infection with antibiotics.

# CARD11 Gain of Function
- Caspase recruitment domain-containing family member 11 (CARD11) is a scaffold protein which plays a crucial role in antigen receptor induced NF-kB activation, B cell differentiation, and functioning of effector T cell.
- CARD11 gain of function mutations are associated with a disorder known as B cell expansion with NF-kB and T cell anergy (BENTA) disease.
- Patients present with enlarged lymph nodes and splenomegaly at infancy.
- Mutation leads to congenital B cell lymphoproliferation, impaired T cell response to antigen receptor activation, decrease in number of immunoglobulins, recurrent sinopulmonary infections, decreased response to vaccines and malignancies due to overactive NF-kB.
- No definitive treatment, patients are monitored and treated for infections and in a few cases via splenectomy to decrease B cell load.