Immunodeficiency

Immunodeficiency can arise from an intrinsic defect of a component of the immune system (primary immunodeficiency or PID). Alternatively, immunodeficiency may be secondary to another pathological condition, which adversely affects immune function. Both primary and secondary immunodeficiency results in increased susceptibility to infection. The precise pattern of infection depends on the specific component of the immune system that is affected. Most PIDs are caused by defects in single genes and hence heritable. Other may represent the consequence of an interaction between genetic phenotype and an environmental influence, like viral infections.

A. Disorders characterized by antibody deficiency

1. Antibody deficiency associated with absent B cells

B–cell maturation beyond the pre–B–cell stage found in the bone marrow, requires signals received through the pre–B–cell receptor complex. The pre–B–cell receptor is composed of the µ chains, surrogate light chains (heterodimers of λ constant region with V pre–β), and the signal–transducing components Igα and Igβ. The activities of the protein BTK (Bruton’s tyrosine kinase) and BLNK (B–cell linker protein) are also essential for the transduction of signals received via the B–cell (and pre–B–cell) receptors. Therefore, it is not surprising that mutations in each of these elements causes early–onset antibody deficiency associated with lack of circulating B cells.

Ninety percent of all such cases occur in boys due to mutation of the BTK gene, which maps to the X chromosome (Xp22). This condition is called X– linked agammaglobulinemia. Mutations in the genes,µ ,5, Igα, Igβ, and BLNK cause rare autosomal recessive forms of early–onset antibody deficiency with severe lymphopenia.

2. Antibody deficiency due to defect in immunoglobulin isotope switching

During primary antibody responses, B cells initially produce IgM and later on in the response switch to the production of IgG, IgA and IgE.

During the so called immunoglobulin class–switching process, the heavy chain constant region changes while antigen specificity is maintained. Immunoglobulin class switch takes place within B–cell follicles of the secondary lymphoid organs. Another process that occurs within germinal centers is somatic hypermutation, which results in the sequential accumulation of point mutations in the Ig variable region gene. If the point mutation result in increased binding affinity to the inducing antigen, the B– cell blasts (centrocytes) survive, proliferate, and eventually give rise to memory B cells and plasma cells that secrete high–affinity antibody (this process is called affinity maturation). Through these processes, memory B cells are generated within germina centers.

Defects in genes encoding molecules required for the above processes, which operate within germinal centers, result in a form of antibody deficiency with elevated (or normal) IgM levels but lacking IgG, IgA, and IgE. These conditions are called hyper–IgM (HIGM) syndromes. A key requirement for germinal center formation and function is the interaction of CD40 (belonging to the TNF–receptor superfamily) found on the surface of B cells with an “activation induced,” CD40–ligand (CD40L) protein expressed on the surface of CD4 lymphocytes. Mutations in the CD40L gene or the CD40 gene result in X–linked and autosomal recessive HIGM, respectively. Patients with the CD40L deficiency suffer from recurrent bacterial infections typical of antibody deficiency. However, because CD40L function is required for optimal T–cell immunity, they also suffer from opportunistic infections characteristics of T–cell deficiency. About a third of patients with CD40L deficiency develop Pneumocystis pneumonia. Infections with cryptosporiodosis, toxoplasmosis, and nontuberculous mycobacteria also occur in this condition. These opportunistic infections can be explained on the basis that the interaction of CD40L on activated T cells with CD40 expressed on the surface of macrophages and dendritic cells, which in turn undergo maturation and activation, is required for the optimum expression of antimicrobial immunity.

A high proportion of CD40L–deficient patients develop progressive liver damage (sclerosing cholangitis), probably the result of cryptosporidial infection of the bile duct.

Defects in the RNA–editing enzymes, activation–induced cytidine deaminase (AID), and uracil–DNA glycosylase (UNG) result in two further types of HIGM syndromes, which are defective class switching and affinity maturation.

Signaling through CD40, which belongs to the TNF–receptor superfamily, depends on the activation of the inhibitor of κ kinase (IKK) complex, resulting in the induction of NFκB. Hypomorphic mutations of the gamma subunit of the IKK complex, which is called NEM (NFκB essential modulator), impairs NFκB activation. Patients with mutations in NEMO develop a complex immunodeficiency, which includes features of the HIGM syndrome.

3. Common variable immune deficiency

Most patients with primary antibody deficiency are collected under this heading which is a condition characterized by low serum IgG and IgA and a variable decrease in IgM and the impaired production of specific antibodies following natural microbial exposure or immunization.

The immunological phenotype of CVID is heterogeneous with documented defects in B–cell survival, generation of B memory cells, and in vitro B– and T –cell activation.

a. The most common defect (in approximately 10% of CVID patients) is a mutation of the gene TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor). TACI is a ligand for the cytokines, BAFF (B–cell–activating factor of the TNF family) and APRIL (a proliferation–induced ligand), which induce immunoglobulin class–switch recombination.

Mutations in TACI have been found in CVID patients and their relatives, with selective IgA deficiency, indicating variable penetrance of this gene defect. In the majority of currently documented patients, TACI mutations affect only one allele, indicating a dominant negative effect of the mutated gene. A possible explanation is that TACI undergoes ligand independent preassociation and function as multimeric units. Thus incorporation of a mutated TACI chain in this multimeric complex may disrupt ligand binding or signal–transducing capacity.

b. ICOS (inducible co–stimulating receptor) is a co–stimulatory T–cell molecule that induces cytokines required for supporting class–switch recombination, Ig production and terminal B–cell differentiation. Mutations in the ICOS gene account for about 1 percent of CVID patients.

c. CD19 is a B–cell accessory molecule that is required for B–cell activation, proliferation, and hence B–cell development. Several cases have been reported with CVID.

4. IgA Deficiency

IgA deficiency is characterized by reduced (<0.07 g/L) or absent serum IgA levels. IgA deficiency is the most common form of primary antibody deficiency and affects 1 in 700 Caucasians. The majority of IgA–deficient individuals remain free of infection due to the ability of IgG and IgM to compensate for the lack of IgA. Long–term studies have shown that a small proportion of IgA–deficient patients develop recurrent sinopulmonary or gastrointestinal infections. Most infection–prone IgA–deficient patients have concomitant IgG2 subclass deficiency and a selective inability to produce antibodies against bacterial capsular polysaccharides.

IgA deficiency is associated with an increased incidence of atopy, celiac diseases, and a range of autoimmune diseases, including arthritis, “lupus– like” syndrome, autoimmune endocrinopathies, and autoimmune cytopenias.

IgA deficiency and CVID can differentially affect members of the same kindred. Rarely, IgA deficiency can precede the development of CVID. Therefore, in some instances, the molecular mechanisms underlying CVID and IgA deficiency may be identical. TACI deficiency can cause IgA deficiencies in some family members while develop CVID.

Genetic analysis of kindred with CVID and IgA deficiency has highlighted the existence of susceptibility loci within the MHC region of chromosome 6. The strongest linkage lies within the DR/DQ within the MHC class II region.

5. IgG subclass deficiency

Serum IgG comprises four subclasses called IgG1, IgG2, IgG3 and IgG4 reflecting the relative abundance of these isotypes in the serum.

Some individuals with IgG subclass deficiencies are asymptomatic. Others with IgG subclass deficiencies are prone to recurrent sinopulmonary infections. Such infection–prone patient exhibit reduced antibody responses to bacterial capsular polysaccharides. Defective anti–polysaccharide antibody responses are most often seen in individuals with IgG2 subclass deficiency with or without concomitant IgA deficiency. The molecular mechanisms underlying IgG subclass deficiencies are unknown.

B. Defects in cell–mediated immunity (T–cell dependent immunity)

Patients with impaired T–cell function may develop the following:

1. They show increase susceptibility to infections with intracellular microbial pathogens (viruses, intracellular bacteria and protozoa).

2. Viral infections: Infections with exanthematous viruses (measles, chicken pox) can be fatal in children with T–cell deficiency. These viruses are not a problem in adults as they have residual protective antibody responses generated by primary infection or immunization. Adult with T–cell deficiency are typically affected by the reactivation of latent viruses which can produce life– threatening disseminated infections.

3. Fungal infections:

a. Pneumocystis giroveci causes interstitial pneumonia, which is pathogenic for T–cell deficiency.

b. Mucocutaneous infection with Candida

c. Systemic infections with filamentous fungi

d. Meningitis or systemic infection caused by Cryptococcus neoformans.

4. Intracellular bacterial infection is a particular problem in T–cell–deficient patients. There patients are highly susceptible to infection with M. tuberculosis or reactivation of latent tuberculosis. They are also susceptible to disseminated infection with poorly pathogenic mycobacteria.

5. Infants with T–cell deficiency are usually lymphopenic and fail to thrive.

6. Infants with SCID may develop dermatitis and hepatosplenomegaly due to graft–versus–host disease caused by maternal lymphocytes that have crossed the placenta.

7. Malignancies: T–cell–deficient individuals are prone to develop a range of malignancies where viral infection acts as a co–factor. There is also an increase in cutaneous malignancies occurring in an individual exposed to significant amounts of ultraviolet light (basal–cell carcinoma and squamous carcinoma).

C. Combined T–cell and B–cell deficiencies

Severe Combined Immunodeficiency (SCID)

SCID comprises a group of inherited diseases characterized     by a severe deficit in T-cell development and function with        variable defects in B-cell and natural killer or NK cell                development. SCID leads to death within the first two years     of life, unless patients are rescued by hematopoietic stem        cell transplantation (HSCT). 

These patients typically present in the first year of life with failure to thrive and recurrent infections caused by bacterial, viral and fungal pathogens. Infections typically affect the respiratory and gastrointestinal systems. The infections may be caused by common pathogens as well as opportunistic organisms of low–grade virulence. Live vaccines such as BCG can lead to disseminated life– threatening infections. The persistent infections developing in SCID patients rapidly lead to malnutrition, grown impairment, and early death. Because of the patient’s inability to reject allogenic cells, graft–versus–host (GvHD) can be caused by transplacentally acquired maternal lymphocytes or by allogeneic cells following blood transfusion. GvHD manifests as skin rashes or hepatosplenomegaly and lymphadenopathy.

The absence of tonsils or other lymphatic tissue may be evident and radiographic studies may reveal thymic–hypoplasia. Lymphopenia (absolute lymphocyte count <3 x 10⁹/L in the first year of life) is a characteristic feature seen in over 80 percent of patients with SCID.

Immunological and Molecular Classification of SCID

1. Patients lacking T cells with normal or increased B cells: T – B + SCID

X–linked SCID, which is the most common form, is due to a mutation of the gene encoding the IL–2 receptor Ɣ chain, which is the signal – transducing chain common to the receptors for six cytokines (IL–2, IL–4, IL–7, IL–9, IL–15 and IL–21). The absence of responses to these cytokines causes defects in a broad range of T– and B–cell functions. IL–7 is required for early stages of T– cell development; Lack of response to this cytokine results in T lymphopenia. IL–15 is required for NK–cell development and its lack results in the failure of NK–cell development. Signal transduction through the aforementioned cytokine receptors involves the interaction of the common Ɣ chain with the tyrosine kinase JAK3. This explains why mutations of the JAK3 gene result in an autosomal recessive form of SCID, with phenotype similar to X–linked SCID. Mutations of the α chain of IL–2 or IL–7 receptors result in two rare forms of SCID.

T– and B–cell receptors consist of invariant signal–transducing elements combined with elements that make up the variable regions, which contribute to the antigen–binding portion of the receptor. The gene recombination required for generating these receptors requires the function of the product of recombination activating genes 1 and 2 and a number of proteins that are required for DNA repair.

a. Mutations in proteins required for normal functioning and signal transduction through the T–cell receptor (TCR) cause rare forms of SCID. Mutations of the tyrosine phosphatase, CD45, which helps to initiate signaling by the TCR. Mutation of components of CD3–complex (CD3 Ɣ,ε and δ) result in a SCID phenotype. During signal transduction via TCRs, the protein tyrosine kinases Lck and ZAP70 are required for phosphorylation of ITAMs on the intracytoplasmic segment of the TCR.

2. Patients lacking T and B cells: T – B – SCID

T–B–SCID is commonly caused by mutations of the recombinase–activating– genes, RAG1 and RAG2.

a. RAG1 and RAG2 are enzymes responsible for introducing double stranded DNA breaks, which initiate V(D)J gene rearrangements, required for generating T– and B–cell receptors for antigen. Without normal RAG1 and RAG2 function, T– and B–cell development is arrested in ontogeny, producing T–B–SCID.

b. Hypomorphic mutations of RAG1 or RAG2 result in a leaky form of SCID called Omenn’s syndrome. In Omenn’s syndrome, a few T– and B–cell clones may be generated but the full T– and B–cell repertoire fails to develop. The few T– and B–cell clones that leak through may undergo secondary expansion. As a result, patients with Omenn’s syndrome may not be markedly lymphopenic but the lymphocyte repertoire is oligoclonal and severe immunodeficiency is the outcome.

c. A protein called ARTEMIS is required for DNA repair, including the repair of DNA breaks generated during V(D)J recombination. V(D)J recombination is responsible for T– and B–cell antigen receptor assembly. Mutation of the gene encoding ARTEMIS results in a rare form of T–B–SCID. These patients also exhibit increased sensitivity to ionizing radiation.

d. Adenosine deaminase (ADA) is an enzyme required for the salvage of nucleotides with lymphoid cells. The lack of ADA causes the accumulation of toxic metabolites of adenosine (deoxy–adenosine and deoxy–ATP) within lymphoid cells, resulting in their demise. ADA deficiency results in profound lymphopenia affecting T cells, B cells and NK cells. Rarely, mutations of ADA causing milder forms of enzyme deficiency lead to a milder form of combined immunodeficiency presenting at a later stage in life.

e. Purine nucleoside phosphorylase (PNP) is an enzyme required for purine salvage within lymphocytes, and PNP deficiency causes a milder phenotype of SCID than seen in ADA deficiency.

f.  Cell–surface expression of MHC class I molecules fails if either of the two transporters of antigenic peptides (TAP1 or TAP2) is lacking. TAP1 or TAP2 help to transfer peptides from the cytosol into the endoplasmic reticulum, for subsequent loading onto newly synthesized MHC class I molecules. In the absence of peptide loading, MHC class I molecules are degraded before reaching the cell surface. In the absence of MHC class I antigen expression, CD8 cell function is deficient and these cells are not generated within the thymus. The resulting immunodeficiency is milder than SCID and often presents in later life. Paradoxically, viral infections are not a problem in these patients. Some MHC class I deficient patients develop progressive bronchiectasis, while others develop vasculitis affecting the face and upper respiratory tract. It has been postulated that vasculitis seen in these patients may be due to self–destruction of vascular endothelial cells by the unrestrained cytotoxicity of NK cells.

g. MHC Class II deficiency results in a profound failure of CD4 cell functions. Lack of thymic CD4⁺ CD8^– cell selection for survival results in peripheral CD4 lymphopenia. Because CD4 function is required for normal cell–mediated immunity, as well as antibody production, MHC class II deficiency results in a severe form of SCID with a fatal outcome. MHC class II deficiency is due to mutation in one of four transcription factors (RFXAP, CIITA, RFX5, RFXANK), which regulate MHC class II expression.

h. DiGeorge’s Syndrome (DGS) or Thymic Aplasia or Catch 22 Syndrome is secondary to a hemizygous deletion of the short arm of chromosome 22 (DEL 22q. 11.2). This chromosomal defect causes a complex inherited syndrome characterized by cardiac malformation, thymic hypoplasia, palatopharyngeal abnormalities with associated velopharyngeal dysfunction, hypoparathyroidism, and facial dysmorphism. About 20% of individuals with 22q deletion have thymic aplasia, resulting in T lymphopenia and impaired CMI. In most such cases, the degree of T lymphophenia is modest (partial DGS) and almost complete restitution of the T–cell repertoire and function occurs by two years of age. Therefore, infections characteristic of T–cell deficiency are rare in these individuals. A minority of infected individuals (<1 percent) exhibit profound T lymphopenia, associated with opportunistic infections and a poor outlook unless rescued with fetal thymic transplant.

The 22q. 11.2 regions contain the TBX1 gene, which belongs to the T–Box family of genes that incorporate proteins that regulate embryonic development. Patients with mutations in the TBX1 genes also develop the clinical features seen in 22q. 11.3 deletion syndromes, suggesting that haplo –insufficiency of the TBX1 gene may be responsible for the clinical features seen in those with a deletion of the 22q.11.2 region.

     

D. Phagocyte Deficiencies

Neutrophils are the principal circulating phagocyte. During inflammation, neutrophils become activated and migrate into the tissues where they ingest, kill, and digest invading bacteria and fungi. Neutrophil function can be deficient because of a reduction in the number of circulating neutrophils (neutropenia) or due to inherited defects in neutrophil function.

1. Neutropenia

Neutropenia is defined as a decrease in blood neutrophil count below 1.5 x 10⁹/L. While mild neutropenia may be asymptomatic, severe neutropenia (counts <0.5 x 10⁹/L) is invariably associated with the risk of life–threatening microbial sepsis caused by a broad range of endogenous Gram–positive bacteria and Gram–negative bacteria as well as fungi. Neutrophils are particularly important for maintaining the integrity of mucous membranes. Hence, oral ulceration and perianal inflammation can be features of severe neutropenia. 

2. Defects in Leucocyte Migration

a. To reach the sites of inflammation, neutrophils need to migrate across the endothelium into sites of inflammation. For this process to be initiated, sialyl Lewis^x, which is expressed on the surface of leucocytes, needs to interact with E selectin, which is expressed on the luminal surface of the endothelial cells. Leucocytes, which are transiently arrested by the previous interaction, need to bind tightly to the endothelial surface by a second set of interactions. This is between the protein lymphocyte function–associated antigen–1 (LFA–1). LFA–1 expressed on the leucocyte surface and its ligand intercellular adhesion molecule–1 expressed on the luminal surface of activated endothelial cells. Leucocyte emigration into the tissues follows these adhesion events. LFA–1 is one of a set of three cell–surface heterodimers composed of a common β chain (CD18) with three separate α chains called CD11a, b and c. CD18–CD11a heterodimers from LFA–1, CD18/CD11b heterodimers form complement receptor 3, and CD18 combined to CD11c forms complement receptor 4. LFA–1 is required for leucocyte adhesion to endothelial cells while CR3 and CR4 act as receptors for activated complement, aiding ingestion of opsonized microorganism. Mutation of the gene coding CD18 (resulting in the lack of expression of LFA–1, CR3 and CR4) results in an inherited primary immunodeficiency called leucocyte adhesion deficiency type 1 (LAD1).

b. Mutations of the enzyme GDP–fucosyl transferase prevent post– transcriptional fucosylation of proteins. Such individuals cannot synthesize sialyl Lewis^x. This condition is called leucocyte adhesion deficiency type 2. Leucocytes of the patient with LAD1 and 2 exhibit impaired ability to adhere to endothelial walls and therefore cannot migrate to infected sites.

Click here for full discussion of Lewis Blood Group

The patients typically present in early childhood with recurrent pyogenic infection of skin, respiratory, and gastrointestinal tracts as well as mucous membranes. Poor wound healing and delayed umbilical cord separation are typical. Because of impaired neutrophil migration, these patients develop a leukocytosis and pus fails to form at sites of infection. These inherited disorders are typically associated with severe gingivitis and periodontal disease, again indicating the particular importance of normal neutrophil function for maintenance of the health of the dental crevice. Bone Marrow Transplant is curative in LAD1 and oral fucose supplementation is beneficial in LAD2.

3. Defects in Bacterial Killing

a. In normal, neutrophils (and monocytes), bacterial phagocytosis results in the activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which produces superoxide and generates a mileu within the phagosome that activate the proteolytic enzymes, cathepsin, and elastase. The activity of the proteolytic enzyme is bactericidal. The NADPH oxidase complex comprises two membrane– associated proteins, p91phox and p22phox (also called the α and β units of cytochrome B558, respectively), complexed with three cytosolic cofactors, p47phox, p40phox and p67phox. Mutations have been identified in four out of five components (p91phox, p22phox, p47phox, p67phox), resulting in defective NADPH oxidase activity, leading to impairment of bacterial killing by phagocytic cells. The result is a clinical syndrome, called CGD, characterized by failure of bacterial degradation in vivo, resulting in the persistence of tissue inflammation with granuloma formation in a variety of organs. CGD due to p91phox deficiency is X–linked, while the other variants of CGD are inherited in an autosomal recessive manner.

b. In CGD, the bacterial killing mechanisms that depend on the phagocyte oxidase system are inoperative, but the nonoxidative killing mechanisms are still intact. Therefore, patients with CGD are not troubled by the broad range of microbes that are neutropenic patient would be susceptible to. Instead, CGD patients get infections with a restricted range of microorganisms, which are only susceptible to the bactericidal mechanisms initiated by NADPH oxidase activation. Characteristic sites of infection include subcutaneous tissue, lymph nodes, lungs, and liver. Oral and perioral ulceration are common.

c. The cystolic GTPase Rac2 is required for the normal actin polymerization and optimal function of the phagocyte oxidase system. Rac2 deficiency results in impaired neutrophil mobility and poor superoxide responses to some stimuli.

4. Defects in Killing of Intracellular Bacteria by Activated Macrophages

a. Some bacterial species (Mycobacteria, Listeria, Salmonella) are resistant to the killing mechanisms operating within phagocytic cells and therefore can survive and multiply within monocytes and macrophages. Effective immunity against these organisms depends on T–cell– (and NK–cell–) dependent macrophage activation. Studies in gene–disrupted mouse and human immunodeficiencies have identified that IL–12– and IL–23–dependent interferon gamma (IFN–Ɣ) production is critically important for immunity against intracellular bacterial pathogen. This process is initiated by the stimulation of Toll receptors on the surface of antigen–presenting cells by bacterial ligands such as mycobacterial lipoarabinomannan. This results in the secretion of IL–12 and IL–23 and TNF–α by the antigen–presenting cells. Binding of IL–12 and IL–23 to their respective receptors, expressed on the surface of activated T cells and NK cells, induces these cells to secrete a further cytokine IFN–Ɣ. IFN–Ɣ acting in concert with TNF–α activates macrophages, which are then capable of killing intracellular pathogens.

b. The Mendelian susceptibility to Mycobacterial Disease (MSMD) is group of mutated genes responsible for production or response to IFN–Ɣ. The mutation have been identified in:

(1) The P40 subunit shared by IL–12 and IL–23 (also called IL12B)

(2) The β chain shared by the IL–12 and IL–23 receptors

(3) The TYK2 kinase required for signaling via the IL–12 receptor

(4) The α and β chains of the IFN–Ɣ receptor (IFN–ƔR1 and IFN–Ɣ2)

(5) The STAT–1 signal transducing molecule, which is required for signaling through IFN–Ɣ receptor.

(6) The seventh defect responsible for increased susceptibility to mycobacterial infection is that NFκB essential modulator gene, which is required for NFκB activation, which is critical for signal transduction via the Toll, IL–1, and TNF–α receptors.

Click here for full discussion on Mycobacteria

E. Complex Immunodeficiency due to Miscellaneous defects

1. Wiskott–Aldrich Syndrome

Patients with Wiskott–Aldrich Syndrome typically develop eczema; purpura due to thrombocytopenia and small–sized, defective platelets; and variable immunodeficiency. Antibody production to bacterial capsular polysaccharides is deficient. Patients therefore commonly develop recurrent sinopulmonary infections. T–cell and NK–cell function is deficient and progressive T lymphopenia develops with time. Hence, patients can develop opportunistic infection. Risk of malignancy (especially leukemias or EBV– induced lymphomas) is increased in these patients.

The defective gene, which is on the X chromosome, encodes for the Wiskott– Aldrich syndrome protein, which regulates actin polymerization, and therefore cytoskeletal change is required for normal platelet and lymphocyte function.

2. Ataxia Telangiectasia (AT)

Ataxia Telangiectasia is a condition characterized by cerebellar ataxia, oculocutaneous telangiectasia, growth retardation, and variable immunodeficiency. AT patients show increased sensitivity to ionized radiation and radiomimetic drugs. Increased susceptibility to leukemias and lymphomas is also a feature of this syndrome. Patients often fail to produce antibodies to bacterial capsular polysaccharides and therefore develop sinopulmonary infections. Chromosomal translocations, involving immunoglobulin heavy–chain and TCR loci, are often detected in the T cells of AT patients.

The function of the protein encoded by the affected gene (called ataxia telangiectasia mutated, or ATM) is to detect double–strand breaks in DNA, initiating their repair. Mutated ATM results in defective control of the cell cycle. This explains the radiation sensitivity, abnormal immune cell development and function, and the cytogenetic abnormalities seen in AT.

3. Nijmegen breakage syndrome

Nijmegen breakage syndrome, which is phenotypically similar to AT, is due to a mutation of the NBS1 gene that encodes a protein that acts as a substrate for ATM. DNA–ligase I defect, which also results in defective DNA repair, manifests with growth retardation and immunodeficiency. The product of the MRE11A gene is another component of the DNA damage sensing machinery. Mutaion of the MRE11A gene results in a condition similar to AT.

F. Immunodeficiency resulting in defective homeostasis of the immune system

1. Defects in the Cytolytic Pathway

a. The homeostasis of immune responses requires prevention of excessive lymphocyte activation. The mechanism by which such regulation occurs includes activation–induced cell death of T lymphocytes, which requires the activation of apoptotic pathways. Defects in critical components of these pathways result in susceptibility to hemophagocytic lymphohistiocytosis (HLH), which is usually triggered by an intercurrent viral infection caused by viruses such as EBV or cytomegalovirus. HLH is characterized by massive infiltration of organs, such as the liver, spleen, bone marrow, and central nervous system, by activated CD8⁺ lymphocytes and macrophages, as well as a massive overproduction of IFN–Ɣ and TNF–α. Severe pancytopenia is typical of this syndrome and is caused in part by phagocytosis of blood cells by activated macrophages and in part is secondary to the infiltration of bone marrow by activated macrophages (histiocytes).

b. A number of genetic defects that affect the efficiency of T–cell and NK–cell mediated cytolysis can predispose to the development of HLH. Cytolysis by T cells and NK cells is initiated by the secretion of contents of cytolytic granules at the immunological synapse between the T cells and the target cells. The process involves the translocation of perforin–containing lytic granules onto the target cell interphase, followed by fusion of these granules with the plasma membrane of the T cell, with release of perforin onto the surface of the target cell. Perforin punches holes in the target cell membrane, causing cytolosis.

c. Mutation of the perforin (PRF1) gene, which encodes for perforin, is one of the genetic defects that predisposes to familial HLH. Perforin–supported cytolysis (by CD–8 cells and NK cells) may damp down immune responses triggered by viral infections by aiding the elimination of antigen–presenting cells or by promoting activation–induced death of T cells.

d. Studies of rare immunodeficiency syndromes, all of which are characterized by an increased tendency to develop HLH have identified a number of components required for the normal expression of cytolytic capacity by T cells and NK cells. The intracellular migration and docking of lytic granules requires the function of the small Rab GTPase, RAB27, which is mutated in the Griscelli syndrome characterized by partial albinism, immunodeficiency, and susceptibility to developing HLH. Defective cytolytic granule exocytosis is also a characteristic of patients with mutations of the gene encoding the protein MUNK13–4 (UNC13D). The tSNARE syntexin 11, which is present in the trans–Golgi network, is also in intracellular vesicle trafficking. Mutation of these two genes is responsible for a further form of familial HLH.

e. Lysosomal trafficking regulator is deficient in individuals with a mutation in CHS1 gene. This causes a defect in sorting of cytolytic proteins into secretory granules. This is the underlying defect in the condition called Chediak–Higashi syndrome, which is another condition characterized by susceptibility to HLH.

2. Immunodeficiency characterized by increased susceptibility to EBV infections

a. XLP (X–linked lymphoproliferative disorder) is a rare inherited immunodeficiency characterized by life–threatening pathological processes triggered by EBV infections. The manifestations of this condition include fulminant infectious mononucleosis, virally induced HLH, hypogammaglobulinemia, and the propensity to develop malignant lymphomas. Mutation in the gene SH2D1A encoding the signaling lymphocyte activation molecule (SLAM) associated protein (SAP) are responsible for more than 60% of cases of XLP.

b. Patients with XLP also lack NK T–cells. Therefore, it is possible that NK T–cell function is essential for controlling EBV infection as well as homeostasis of T–cell responses to this virus. Further support to this theory comes from the recent observation that XLP can also be caused by mutation in the gene (BIRC4) that encodes for the protein X–linked inhibitor of apoptosis (XIAP).

c. The pathological manifestations of the XLP cannot be completely attributed to the reduced NK– and T–cell function seen in this condition. The SAP, which acts as a signaling adaptor molecule within lymphoid cells, and XIAP, which regulates apoptosis, helps in the homeostasis of immune responses in complex ways. Therefore, mechanisms underlying the pathogenesis of XLP are likely to be complicated.

3. Immunodeficiency characterized by increased liability to develop autoimmunity

a. The product of the FOXP3 gene is required for the generation and the function of CD4⁺ CD25⁺ T–regulatory cells. Expression of ectopic FOXP3 confers suppressive function on CD4⁺ and CD25⁺ T cells. Human males with mutations of the FOXP3 gene (which is located on the X chromosome) develop a syndrome characterized by neonatal endocrinopathies (including type I diabetes) enteropathy, eczema, immune thrombocytopenia, and cachexia. In these patients, pancreatic islet cell and intestinal mucosal damage are secondary to infiltration of the tissues with mononuclear cells and plasma cells, signifying an autoimmune pathogenesis. This condition is called the immune dysregulation polyendocrinopathy and enteropathy, X–linked (IPEX) syndrome. This condition provides evidence supporting current concepts on the role of T–regulatory cells in preventing autoimmunity.

Recently, mutations in the IL2R gene encoding for the α chain of the IL–2 receptor have been described in patients with the clinical phenotype of the IPEX syndrome. CD4 T cells of these patients fail to produce the immunosuppressive cytokine IL–10.

b. Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare disease caused by defective cellular apoptosis. Apoptosis maintains homeostasis in the immune system by minimizing autoimmune reactions to self– antigens, as well as limiting the total size of the peripheral lymphocyte pool. Failure of lymphocytes to undergo apoptosis results in impaired homeostasis of the lymphoid population. Patients develop lymphocytosis, hyperplasia of lymphoid organs (spleen, lymph nodes), hypergammaglobulinemia, and autoimmunity (autoimmune cytopenias, Guillain–Barre syndrome). Peripheral blood and peripheral lymphoid tissues characteristically contain an increased population of TCR α β positive CD4^– and CD8^– cells (double negative T cells).  Mutations in the FAS–mediated pathway of apoptosis are responsible for most cases.

c. Caspase 8 deficiency causes impaired CD95–mediated apoptosis as well as a defect in T–, B–, and NK–cell function, manifesting as an immunodeficiency. Recently, an activating mutation in the NRAS gene encoding a GTP–binding protein with a broad spectrum of signaling functions has been found in other patients with ALPS. Defective, IL–2 withdrawal induced, apoptosis of lymphocytes is a characteristic abnormality in these patients.

4. Autoinflammatory syndromes

The cleavage of pro–IL–1b to its active product IL–1 by the action of caspase– 1 (interleukin converting–enzyme) is a key event in the generation of an acute inflammatory response. The best–characterized adaptor protein is called ASC (apoptosis–associated speclike protein with a caspase recruitment domain). Mutation of components of this system (also called inflammasone) gives rise to most inflammatory syndromes.

The net effect of all these mutations is to impair homeostasis of the pro– inflammatory cytokine IL–1, NFκB activation, and cellular apoptosis. Impaired cellular apoptosis leads to the persistence of activated leucocytes that would otherwise undergo apoptosis, leading to the resolution of inflammation. Collectively, these abnormalities permit the inappropriate amplification and persistence of inflammatory responses leading to the clinical features of the autoinflammatory syndromes.

5. Inherited deficiency of the complement system

The key event in complement activation is the proteolytic cleavage of C3 to C3a and C3b. Three pathways can lead to C3 cleavage, namely: classical, alternative and mannose–binding lectin (MBL) pathways. C3 cleavage leads on to the activation of the terminal complement pathway, causing the generation of the membrane attack complex (MAC), which assembles a lipophilic complex capable of lysing plasma membranes of susceptible cells.

The inability to generate sufficient CD3b results in increased susceptibility to pyogenic sepsis, especially infections caused by encapsulated bacteria. C3 deficiency may be due to complement utilization or rarely autosomal recessive C3 deficiency. Factor I deficiency also leads to profound CD3 cleavage. Hereditary C2 deficiency and less commonly inherited C4 deficiency may also be associated with the risk of pneumococcal sepsis.

Protection from Neisserial infection requires the ability to generate the MAC, which lyses these bacteria. Patients with inherited homozygous deficiency of C5, C6, C7, C8 and C9 are susceptible to recurrent meningococcal infections. Primary or secondary CD3 deficiency, which in turn reduces the ability to generate MAC, also results in increased susceptibility to meningococcal infection.

MBL deficiency may arise because of one of the three point mutations in the gene encoding for this protein.

6. Complement deficiency and autoimmunity

Under physiological conditions, activation of the classical complement pathway helps in the clearance of the circulating immune complexes by the resident macrophages of the reticuloendothelial system. The surface of apoptotic cells activates the classical complement pathway, leading to their efficient clearance by phagocytic cells expressing complement receptors, preventing the generation of autoimmune responses to cellular components.

Deficiency of components requires for generating the classical partly C3– convertase may result in impairment of the process for eliminating immune complexes and “safe” disposal of apoptotic cells. This would explain the increased incidence of SLE–like disorders in patients with inherited C1q, C1r, C1s, C4, C2, C3, factor I, or Factor H deficiency.

7. Factor H Deficiency

Complete or partial factor H deficiency is associated with the occurrence of the hemolytic–uremic syndrome although the exact mechanism is unknown.

8. Cell–surface–based inactivators of complement

CD59 and CD55 are cell–surface molecules anchored by glycosylphosphatidylinositol. These two proteins inactivate any C3 convertase molecules deposited on cell surfaces. Somatic mutation of the enzyme (PIGA: phosphatidylinositol glycan class A), needed for generate phosphatidyl–inositol anchors for cell–surface proteins, including C55 and CD5, in erythroid precursors, results in a condition called paroxysmal cold hemoglobinuria, which is due to the increased susceptibility of red cells to complement–mediated hemolysis. Isolated CD59 deficiency also results in hemolytic anemia.

Click here for full discussion of Paroxysmal Cold Hemoglobinuria in Blood Banking.

9. C1 Inhibitor Deficiency

a. C1 inhibitor is a serine–protease inhibitor that inactivates the serine esterases generated by complement activation (C1r and C1s), kallikrein of the kinin system, and activated factors XI and XII of the clotting cascade.

b. In the absence of C1 inhibitor, C1 activation results in the depletion of the serum C4 level. C1–inhibitor deficiency also results in the inability to inactivate bradykinin, resulting from the unregulated activity of kallikrein. Production of bradykinin in the tissues results in increased vascular permeability, manifesting as attacks of angioedema.

c. Angioedema of the intestinal tissues results in recurrent episodes of severe abdominal pain due to partial intestinal obstruction, which can mimic an acute abdominal emergency.

d. C1–inhibitor deficiency arises from a heterozygous mutation of C1INH gene, which acts in an autosomal dominant manner. The single normal gene cannot maintain the synthesis of physiologically sufficient quantities of C1 inhibitor. In 85 percent of C1–inhibitor–deficient individuals, the mutation prevents transcription of the defective gene. In 15 percent of affected individuals, the gene mutation abolishes the activity of the secreted protein. Rarely, autoantibodies to C1 inhibitor can lead to acquired C1–inhibitor deficiency.

G. Defects in innate immunity

1. Defective NFκB activation caused by X–linked hypomorphic mutations of the essential modulator gene (NEMO) compromises signaling mechanism downstream of Toll, IL–1 and TNF–α receptors. These patients are susceptible to infections caused by microorganisms.

2. UNC93B is a protein of the endoplasmic reticulum is involved in Toll– receptor activation. Mutations in UNC93B impair the production of INF–α and IFN–β in response to HSV and other viruses. Recently, heterozygous dominant–negative mutations in the gene encoding toll receptor 3 (TLR3) have been identified in patients with Herpes simplex encephalitis. TLR 3 is expressed in the central nervous system where it helps to initiate INF–α and IFN–β responses to viral double–stranded DNA.

3. Interleukin–receptor–associated kinase–4 mediates signaling downstream of Toll receptors and members of the IL–1 receptor superfamily. IRAK–4– deficient individuals present during childhood with recurrent, severe, pyogenic sepsis. They are particularly susceptible to recurrent pneumococcal infections.

4. The signal–transducing molecule STAT–1 is required for signaling via receptors to INF–Ɣ as well as IFN–α and IFN–β. INF–Ɣ–receptor–mediated signaling involves the dimerization of phosphorylated STAT–1 molecules. Signaling via IFN–α and IFN–β receptors involves the formation of a complex between STAT–1, STAT–2, and a third protein called interferon–stimulated– gene factor 3–Ɣ. Complete (homozygous) defects of the signal–transducing molecules STAT–1 results in defective responses to IFN– Ɣ, IFN–α and IFN–β eater leading to the susceptibility to disseminated mycobacterial infections as well as fatal Herpes simplex viral infection. Partial STAT–1 deficiency, which interferes with STAT–1 dimerization required for signal transduction via IFN–Ɣ receptors, leads to increased susceptibility to mycobacterial infections. In these patients, the cellular responses to IFN–α and IFN–β is intact, thus preserving antiviral immunity.

5. The WHIM syndrome is a condition characterized by severe warts, hypogammaglobulinemia and neutropenia. This is the first example of an immunodeficiency caused by aberrant chemokine–receptor function. WHIM syndrome is caused by a mutation in the gene encoding the CXCR 4 chemokine receptor. The mutant form of this receptor shows enhanced responsiveness to its ligand.

6. The hyper–IgE syndrome (HIES) is a complex clinical entity characterized by recurrent bacterial and fungal infections of skin, lymph nodes, lungs, bones, and joints. These patients have elevated serum IgE levels, eosinophilia, dermatitis, facial dysmorphic features, delayed shedding of primary dentition, osteopenia, and impaired acute–phase responses during infections. Most patients have an autosomal dominant inheritance while others are sporadic cases. Patients with classical HIES have heterozygous mutations in the gene encoding the signal–transducing protein STAT–3.