Primary Immunodeficiency Genetic Disorders Biology Essay


Primary Immunodeficiency disorders are a heterogeneous group of genetic disorders, which can affect the innate as well as the adaptive human system and lead to an increased susceptibility to infections. Depending on which cell type(s) are absent or defective, patients will suffer from recurrent infections by different pathogens. Some PIDs are associated with many different pathogens, varying from viruses to fungi, whereas others are linked to an increased susceptibility to one particular virus. Research on these genetic immune disorders has contributed to a better understanding of the human immune response to some of these pathogens. This review will focus on the different types of PIDs and the infections that result due to their susceptibility to various pathogens. A paradigm shift, which has been introduced by the discovery of new PIDs that are caused by mutations in a single gene and affect immunity against primary infections without affecting immunity against secondary infections will be discussed as well.


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Primary Immunodeficiency disorders (PID's) are genetically heterogeneous disorders that can affect all components of the immune system. Although PID's are rare in their occurrence, they can be exploited successfully in order to gain an in-depth view into the functioning of the human immune system. PID's are being used to identify key checkpoints that control the functioning of the human immunity system {Raif, 2007}. Studies that address the molecular pathophysiology of PID's and associated vulnerabilities to infections have contributed to a better understanding of the immune system and aided the development of new therapeutic approaches {Luigi, 2004}. Over 130 distinct genes have been identified and these account for over 150 different forms of PID's. PID's are very complex in terms of their genetics, immunological inhibition, and presentation of clinical symptoms {Raif, 2007}. They have been classified into 5 major types: B-cell disorders, T-cell disorders, Combined B and T-cell disorders, Phagocytic disorders, and Complement disorders.

Immunodeficiency is suspected when physicians are confronted with patients suffering from severe, recurrent and excessive infections. Depending on the mutation that is at the basis of the disorder, the causative agents of the infections vary from a range of opportunistic pathogens to very specific pathogens. In general, patients presenting with pyogenic or pus-forming bacteria suggests that they have defects in antibody, complement or phagocyte function, whereas recurrent viral infections or persistent fungal dermatitis suggest defects in T lymphocyte function. Early diagnosis can save many lifes and goes a long way in improving quality of life of the patients. It also prevents rapid deterioration of the immune system {Catherine, 2002}. In contrast, delayed diagnosis, which may occur due to the complex nature of these disorders, can result in increased susceptibility to infections which can manifest as life-threatening autoimmune complications. These include massive proliferation of certain immune cells, disregulated apoptosis, inflammation, and improper antigen presentation {Chapel, 2003}.

This review discusses the different types of PID's, the infections that occur as a result of these disorders, and offers an in-depth analysis of those diseases that have been associated with very specific pathogens.

1. B-cell disorders:

Primary B cell disorders are a heterogeneous group of antibody deficiency syndromes, ranging from a complete absence of B cells and immunoglobulins to selective IgG subclass deficiencies {Arason, 2010}. Antibodies play an important role in recognizing foreign antigens such as viruses and bacteria, and clear them from the body by agglutination and precipitation of antibody-antigen products, priming of phagocytosis by macrophages and other cells, blocking viral receptors, and stimulating other immune responses, such as the complement pathway. Patients with B cell disorders are particularly susceptible to infections by encapsulated bacteria {Sorensen, 2000}. The infection site and the pathogen involved in the infection helps in the identification of the type of immune deficiency.

A classical B cell disorder, X- linked agammaglobulinimia (XLA) was first described in 1952 by Ogden C. Bruton {Bruton, 1952}. Patients affected by this disease carry mutations in the gene that encodes bruton's tyrosine kinase (Btk), which is located on the X chromosome. 600 different kinds of mutations have been reported in the Btk protein, {Conley, 2009} which include point mutations, large deletions and splicing defects {Jin, 1995}. Btk is a member of the Tec family of kinases and is expressed in all haematopoietic cells with exception of T cells {Pierre, 1999}. Btk is essential for B cell growth, differentiation and signaling. In XLA patients, B cell maturation is blocked between the pro and pre  B cell stages resulting in a loss of peripheral B cells in blood and low serum immunoglobulins {Marron, 2010}. The reduction in cytoplasmic  H chain-expressing pre-B cells in the bone marrow of XLA patients is probably caused by defective pre-BCR signalling as signaling through this receptor controls the expression of a functional  H chain {Middendorp, 2002}.

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Later studies have shown that Btk mutations also affect other components of the immune system. Btk has many domains which are responsible for interacting with proteins critical for intracellular signaling {Vihinen, 1996}. For example, it plays a vital role in toll like receptor signaling (TLR) which is triggered by lipopolysaccharides (LPS). TLR signaling enhances transcription of inflammatory cytokines such as tumour necrosis factor (TNFα) and IL-1β (These genes are transcribed through NFÒ›B which is important for B cell differentiation) {Marron, 2010}.  It was found that in mice having a point mutation in the Btk gene, production of LPS-induced TNFα and IL-1β production was impaired. This in turn lead to improper functioning of immune cells like neutrophils (first cells to reach site of infection) and macrophages. It was also seen that  TLRs like TLR4, TLR7, TLR8 and TLR9 phosphorylate Btk, due to which Btk binds with the main  components of the TLR signaling pathway such as MyD88 (myeloid differentiation protein 88) and IRAK 1(IL-1 receptor associated kinase 1). This shows that Btk has a role both in innate and adaptive immunity {Doyle, 2007}.

Symptoms in XLA patients are seen after 6-7 months of age, as infants have maternal immunoglobulin (IgG) which offers protection against infections {Ballow, 2008}. Ear, nose and throat infections are common symptoms of XLA patients. Recurrent otitis and small or absent tonsils are also commonly seen in XLA patients {Conley, 2002}.

Patients with XLA are prone to get infections caused by pyogenic bacteria such as Streptococcus pneumonia resulting in major mortality and morbidity {Conley, 2009}.  Pyogenic bacteria can escape the removal by the innate immune response as they have polysaccharide capsules which are not recognized by the receptors present on macrophages and neutrophils, required for phagocytosis. Antibodies are required for opsonising the extra cellular pyogenic bacteria by phagocytosis. As there is no antibody production in XLA, infections by streptococcus pneumonia cannot be controlled {Simonte, 2003}.

Patients with XLA are also susceptible to infections by viruses that enter through the gut, such as ECHO virus and poliovirus. Defence against these infections is antibody- mediated. Infections by hepatitis C virus are also seen in XLA patients and are usually due to contaminated blood used for antibody production {Fried, 2009}.

XLA is treated by human antibody infusions, which is sufficient to reduce the severity and number of infections {Gardulf, 2006}. New treatment methods based on gene transfer of the corrective gene are being developed and have been successfully used to treat mouse models of XLA {Kerns, 2010}.

2. T-cell disorders:

T-cell immunodeficiency has a serious impact on the patient's immune response as it affects both humoral and cell-mediated immune responses. This is mainly due to the interaction of T cell subpopulations with macrophages and B cells, and other T cell subsets for activation and termination of the immune responses against pathogens {Fischer, 2001}. The most common T cell disorders are Digeorge syndrome, X-Linked lymphoproliferative syndrome, ZAP-70 deficiency and chronic mucutaneous candidiasis {Notarangelo, 2006}. Patients with T cell disorders are susceptible to infections by various microorganisms, however, viral infections are the most common ones. For patients with T cell immunodeficiency infections with non-pathogenic viruses such as Cytomegalovirus, or even attenuated measles virus as present in the measles vaccine can lead to life threatening disease {Waldmann, 1978}.

A classical T cell disorder, X linked lymphoproliferative syndrome (XLP) is an inherited disorder with an increased susceptibility to Epstein-Barr virus (EBV) infections. EBV is a common human virus of the herpes family that causes infectious mononucleosis. It has also been associated with a number of cancers i.e. Hodgkin's lymphoma, Burkitt's lymphoma, central nervous system lymphomas associated with HIV, and nasopharyngeal carcinoma. XLP is a rare PID, which was first diagnosed in patients with the following clinical triad: infectious mononucleosis, acquired hypogammaglobulinaemia and B cell lymphoma {Lim, 2004}. XLP is caused by mutations in the src homology 2 domain containing gene 1A (SH2D1A) gene. SH2D1A encodes the signaling lymphocytic activation molecule (SLAM)-associated protein SAP, which plays a role in the intracellular signaling of T, natural killer cells (NK cells), NKT cells, platelets and eosinophilis {Sayos, 1998}. 70 different types of mutations are seen in the SH2DIA gene {Marsh, 2010}. These include nonsense mutations, missense mutations and deletion mutations {Nichols, 2005} leading to the failure of SAP expression in immune cells like T cells, NK cells and NKT cells {Veillette, 2008}.

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SAP can interact with 6 of 9 SLAM family cell surface receptors (2B4, NTB-A, SLAM6, SLAM5, SLAM7 and Ly9) which play a role in cytotoxicity, humural immunity, autoimmunity, cell survival, lymphocyte development and cell adhesion. The interaction occurs through the immunoreceptor tyrosine based switch motifs (ITSM) of SLAM. After association of SAP with the ITSM, SAP recruits the protein tyrosine kinase Fyn, which in turn leads to phosphorylation of tyrosin residues in the cytoplasmic part of SLAM. This phosphorylation gives SLAM the ability to act as a docking site for various proteins, therefore influencing downstream signaling cascades which play a role in the aforementioned immunological processes {Hislop, 2010}.  An alternative mode of action is that SAP inhibits the interaction of the ITSM with other SH2 domain containing proteins, thereby influencing downstream signaling cascades. SAP expression appears to be required for NKT cell development as well as for proper functioning of NK cells and CD8+ T cells. In addition, XLP patients have strongly reduced numbers of memory B cells and the few memory B cells that are present have not undergone class switching. This defect together with the observed impaired function of effector CD4+T cells is most likely responsible for the underlying hypogammaglobulinaemia in XLP patients. Thus, the absence of SAP expression in XLP patients has an effect on several aspects of the immune system, however, it is not entirely clear how these defects influence the increased susceptibility to EBV infection {Ma, 2010}.

EBV infection typically leads to a strong but transient expansion of EBV-specific CD8+ T cells, which efficiently control B cell infection. In XLP patients, this response appears uncontrolled resulting in a massive expansion of polyclonal B and CD8+ T cells, which populate bone marrow and liver. This infiltration can lead to bone marrow aplasia and hepatic necrosis {Grierson, 1987}. Studies have shown that CD8+ T cells of XLP patients show lytic defects against EBV+ B cell lines. However, it was not clear whether these T cells were specific to EBV {Dupre, 2005}. Recently EBV specific CD8+ T cells isolated from patients were analyzed for their response. In these patients it was seen that EBV specific CD8+ T cell function was impaired when challenged with EBV+ B cells {Plunkett, 2005}. However, their activity could be restored by blocking interactions of SLAM receptors. Therefore, stating that XLP EBV specific CD8+ T cells can have normal effector function depending on the antigen presentation {Hislop, 2010}. In addition NK cell mediated killing of infected cells is defective in these patients. Studies have shown that they show normal cytotoxic activity when triggered by CD16 receptors but when SAP binding receptors like 2B4 are involved, the NK cell cytotoxicity is impaired. This leads to defective killing of EBV infected B cells expressing SLAM receptors {Bottino, 2001}.

The treatment available at present for XLP is immunoglobulin replacement therapy and bone marrow transplantation {Ma, 2010}. In the future therapies like gene therapy may prove to be useful.

3.  B cell and T cell combined disorders:

T cells assist in maturation of B cells and inhibit B cell development or proliferation when required. It is therefore evident that a major dysfunction of T cells could cause a secondary B cell deficiency in humans {Moraes-Vasconcelos, 2008}. Combined B and T cell disorders account for approximately 20% of primary immunodeficiencies. Cell mediated immune responses, T cell dependent antibody and NK cell responses can be absent in patients with combined T and B cell disorders.  

One of the major combined disorders is a family of disorders called Severe Combined Immune Deficiency (SCID). SCID develops due to underlying defects in T, B and NK cell differentiation and their function. This disorder can be caused by mutations in many different genes. For example, SCID can be caused by mutations in the genes encoding CD45, IL-7 receptor alpha chain, CD 3 delta chain, RAG1 and RAG2, JAK3, adenosine deaminase, common gamma chain and artemis {Fischer, 2000}.The products of these genes are important and are required for the regulation of threshold of signaling in immune cells, prevention of toxic accumulation of metabolic wastes, rearrangement of antigen receptor genes, preventing defects in cytokine mediated signaling and for T cell development {Buckley, 2004}. Defects in cytokine mediated signaling are the main cause of SCID. Patients with SCID are susceptible to gut and respiratory tract infections, caused by Candida albicans, P.Carinii, adenoviruses, Cytomegalovirus, Bacillus Calmette-Guerin (BCG), parainfluenza 3 and Epstein Barr virus leading to growth impairment and malnutrition {Buckley, 1997}. Onset of infection is during infancy and the prognosis is early death unless some medical intervention rebuilds the immune system {Rebecca, 2002}.  

X-linked severe combined immunodeficiency (SCID-X1) is the most common form of severe combined immunodeficiency.  It is also called bubble boy disease. This name was given after a boy suffering from X-linked SCID had successfully lived in a bubble for several years {Leonard, 1996}. Mutations in the common γ -chain (γ c), which is a subunit of several cytokine receptors like interleukin (IL) IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, are at the basis of this disease (T- B+ NK- SCID) {Buckley, 2004}. Patients suffering from this disease lack mature T and NK cells whereas B cells are present in normal or high numbers {Stephan, 1996}. Males with X-linked SCID have recurring infections by certain bacteria, viruses and fungi. Most patients with X-linked SCID show symptoms such as skin rashes, diarrhoea, slow growth and development as compared to normal children {Leonard, 1996}.

As mentioned earlier, SCID-X1 patients, like all SCID patients, are vulnerable to many different pathogens. However, patients with SCID-X1 often undergo a life saving treatment, haematopoietic stem cell transplantation. Post transplantation analysis of these patients has shown that some infections remain present after treatment. This is particularly true for human papillomavirus (HPV). HPV causes non cancerous skin warts mainly on hand and feet. This appears to be due to the NK cell deficiency, as these post-transplantation infections are only observed in patients, which lack NK cells (SCID-X1 and and JAK-3 deficiencies). However, NK cell counts were similar in patients with HPV infection and without HPV infection. This states that the number of cells may not play a role. Alternatively, this phenomenon can be explained by defects in keratinocyte-mediated innate immunity. Keratinocytes express many cytokine receptors with gamma chain subunits and these gamma chain dependent cytokines lead to production of many molecules that have an effect on HPV {Laffort, 2004}.

4.  Primary Phagocytic disorders:

Phagocytes like neutrophils and macrophages play an important role in innate immunity. These cells express toll like receptors, scavenger receptors and opsonin receptors which help them in phagocytosis of foreign phathogen and their products. Infections which are common in many of the PID's are rare in patients with phagocytic disorders {Dale, 2001}. Patients with these phagocytic disorders are susceptible to infections by staphylococcal, fungal, and gram negative microorganisms which will be discussed in this section. There are three types of phagocyte immunodeficiencies: 1) those that are caused due to mutations in genes that play a role in phagocyte production. For example, a mutation in the ELA2 gene causes production of a toxic intracellular protein which blocks neutrophil maturation, leading to severe neutropenias. More specifically, the   mutation in the ELA2 gene affects the enzyme catalytic site and in turn leads to inactive elastase, due to which neutrophil count decreases to very low levels. In addition, other phagocytic cells like monocytes will also be in lower levels. Mutations in the granulocyte colony stimulating factor (GCSF) receptor can also lead to a defective production of granulocytes {Notarangelo, 2010}. Patients with these phagocyte immunodeficiencies tend to get infections by the microorganisms which are found on the body surface. For example, Staphylococcus aureus will cause skin infection, Streptococcus species will cause oral infection, and gram negative bacteria will cause gingivitis {Etzioni, 2001}.

2) The second type of phagocytic disorders are caused by mutations in genes that control phagocyte interaction. For example, deficiencies in leukocyte's integrin common beta2 subunit CD18 does not allow leukocytes to reach the site of infection. This defect prevents the leukocytes to adhere tightly to the endothelium and causes leukocyte adhesion deficiency (LAD) {Uzel, 2008}. Complement mediated phagocytosis and antibody dependent cytotoxicity are also deterred in patients with LAD {Alessandra, 1999}. Patients having this defect are susceptible to infections by Streptococcus aureus and by enteric gram negative bacteria. Also, LAD patients usually have impaired wound healing. Severe distructitive periodontitis and tooth loss are other issues seen in LAD patients. Bone marrow transplantation is the only cure for LAD {Etzioni, 2001}.

3) The third type of phagocytic disorders are caused by mutations in genes that play a role in the killing mechanism of phagocytes, Such defects can lead to the formation of chronic granulomatous disease (CGD). This disease mainly occurs when there are defects in the enzyme complex which plays an essential role in the generation of the superoxide known as reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase {Winkelstein, 2000}. The NADPH oxidase consists of a membrane bound complex which is embedded in the membranes of secondary granules (gp91phox and gp22phox, also called cytochrome b558 ) and four cytosolic proteins called p47phox, p67phox, p40phox and rac. Upon cellular activation, phagolysosome and secondary granule fuse and cause deposition of cytochrome b558 in the membrane. Later, they tightly bind to the cytosolic proteins forming NADPH oxidase. NADPH oxidase transfers an electron to molecular oxygen, which leads to the production of superoxide. Superoxide is very reactive and gets converted to hydrogen peroxide with the help of superoxide dismutase. Later in the phagosome, hydrogen peroxide gets converted into hypohalous acid with the help of myeloperoxidase and chlorine {Rosenzweig, 2004}. Earlier it was thought that the metabolites of superoxide to be responsible for the killing of bacteria, but recently it was shown that superoxide produced by phagocytes activates granule proteins cathepsin G and neutrophil elastase in the phagocytic vacuoles and that these two proteins are required for killing of bacteria {Reeves, 2002}. These results suggest that that the reactive oxidants are important for intracellular signaling of molecules which help in activating other non-oxidative pathways instead of direct killing.

Chronic granulomatous disease (CGD) is mainly caused by mutations in the four structural genes of the NADPH oxidase, gp91phox, p22phox, p67phox and p47phox. Mutations in gp91phox lead to X linked recessive disease and mutations in the other three genes lead to autosomal recessive disease. gp91phox and p22phox need each other for their expression in the phagocytes. gp91phox is only expressed in phagocytes but p22phox is also expressed in other tissues where it binds with other proteins. Therefore patients having the autosomal recessive form of CGD may have abnormalities in other tissues where these proteins are expressed {Holland, 2010}. Patients having CGD are susceptible to recurrent life threating infections mainly due to Staphylococcus aureus, Serratia marcescens, Norcardia, Burkholderia cepacia, Aspergillus, Salmonella, Bacilli Calmette Guerin (BCG) and tuberculosis. The infections mainly affect lung, lymph nodes, liver and skin. Patients having CGD are usually diagnosed early during their childhood as they suffer from infections and develop granulomatous lesions. In CGD patients Staphylococcus aureus infections lead to liver abscesses; Burkholderia cepacia infection causes pneumonia and sometimes sepsis; Aspergillus (fungi) infection causes pulmonary inflammation and leads to mortality. Norcardia infection causes leukocytosis and increases the sedimentation rate of erythrocytes. Serratia marcescens infection causes bacteremia which is very rare {Babior, 2004}. Prolonged interaction with these pathogens triggers a cell mediated response which results in chronic inflammation due to which granuloma formation takes place which in turn leads to development of autoimmune diseases like systemic lupus erythematosus and Crohn's disease {Assari, 2006}.

Prophylactic antibiotics are used to reduce bacterial infections in CGD patients. Interferon gamma (IFN γ) is also used in treatment of CGD patients. IFN γ is a macrophage activating factor which is important for host defence against intracellular infections. IFN γ stimulates the production of tumor necrosis factor α (TNFα) which increases the surface expression of MHC II and of Fc gamma receptor II proteins, which plays a role in increasing phagolysosomal acidification {Schiff, 1997}.  Incubation of granulocytes from patients having CGD with IFN γ, increased the NADPH oxidase velocity and prevented respiratory burst in patients treated with IFN γ {Jackson, 2001}. Gene therapy can be used for CGD treatment as it is a single gene defect, however some complications have been observed {Grez, 2010}.

5. Complement system disorders:

The complement system helps in clearing pathogens by forming a biochemical cascade of the innate immune system. It consists of many different plasma proteins, which upon activation act together to induce cytolysis, chemotaxis, opsonization, immune clearance, and inflammation, as well as the marking of pathogens for phagocytosis {Wen, 2004}.

The complement system consists of three biochemical pathways- the classical pathway, the mannose binding lectin pathway (MBL), and the alternative pathway. Activation of these three complement pathways leads to opsonisation, chemotaxis, inflammation, cytolysis, and immune clearance by phagocytosis {Ram, 2010}. The classical pathway gets activated when antibodies bind to specific antigen and is therefore a specific immune response. It inhibits the formation of insoluble immune complexes in the plasma. The alternative pathway is not dependent on antibody-antigen binding and therefore provides the first line of defence against pathogens before any immune response is formed so it gives a non- specific immune response. It solublizes immune complexes formed or deposited in the tissues {Ricklin, 2010}. The mannose binding lectin pathway (MBL) gets activated once the serine proteases bind to carbohydrate present on the bacterial surface {Takahashi, 2006}.

Primary complement deficiencies are rare autosomal recessive disorders, with the exception of the C1 inhibitor deficiency, which is a dominant autosomal disorder {Warren, 1997}. Complement deficiencies increase the risk of infections and can cause autoimmune disorders. Defects in early components of the alternative pathway and in C3 cause susceptibility to infections by extracellular pathogens, particularly pyogenic bacteria like Streptococcus pneumonia, haemophilus influenza type b and Neisseria species like N. meningitidis. The C3 component undergoes conformational changes by itself, which in turn leads to binding of factor B (C3b). Due to this binding factor B also undergoes conformational changes which allow the serine protease factor D to cleave the C3b complex. This leads to formation of the C3 convertase molecule of the alternative complement pathway (C3bBb) and C3a which is called anaphylatoxin. The C3 convertase is capable of cleaving the C3b molecule, which is an important opsonisation molecule. It has a role in marking the pathogen and helps in phagocytosis, due to which more C3 convertase is formed. This process is known as positive feedback amplification {Mackay, 2001}. This further leads to formation of the membrane attack complex (MAC) by fusion of C5b, C6, C7, C8 and C9. C5a is also obtained during MAC formation, which is a potent anaphylatoxin and chemoattractant, and this leads to type three hypersensitivity and causes tissues damage. The anaphylotoxin obtained activates mast cells and produces histamines and cytokines leading to the formation of inflammation {Haas, 2007}. The assembled MAC leads to the formation of pores on bacterial surfaces allowing the bacteria to be phagocytosed after apoptosis. Properdin is a positive regulator of the complement system and is stabilized by C3 convertase of the alternative complement pathway {Spitzer, 2007}. Gram negative bacteria and fungi have thick cell walls and are resistant to MAC lysis.

The defects in the early components of the classical pathway mainly affect the clearance of apoptotic cells formed due to activation of the alternative complement system and the processing of immune complexes which in turn leads to formation of autoimmune disease like systemic lupus erythematosus {Flierman, 2007}. The apoptotic cells formed are cleared by macrophages and dendritic cells. This is initiated by binding of C1q molecule to antibodies which occurs when the classical complement pathway is activated. The C1q molecule is a multimeric complex and once it binds to antibody, a C4 molecule comes and binds to it and gets cleaved. Later C2 molecules bind and get cleaved, and C3 convertase of the classical complement pathway is formed which cleaves C3 leading to the formation of C5 convertase. Later MAC is formed which plays role in clearing apoptotic cells. Thus, a single C1 complex can cleave many molecules leading to an amplification of complement activation {Gullstrand, 2009}.

Defects in the mannose binding lectin pathway ( MBL) of complement are associated with bacterial infections mainly during childhood as innate immunity is impaired. Carbohydrates are present on pathogen surfaces and carbohydrate binding proteins bind to them. Thus mannose, a carbohydrate which is also present on the pathogen surface and be bound to the mannose binding lectin protein. The mannose binding lectin protein has two serine proteases, MASP1 and MASP2. Once they bind to mannose on the bacterial surface, the MBL pathway gets activated {Takahashi, 2006}. This activation leads to cleavage of C4 and C2 due to which C3 convertase is formed and leads to the formation of MAC.

Defects in the MAC components are associated with increased susceptibility to infections by Nesseria species which causes meningitis and gonorrhoea. This proves that these effector pathways have an important role in the defense against Nesseria species {Szebeni, 2004}.

6. Paradigm shift in PIDs:

Most of the immunodeficiencies affect the protective immunity to primary and secondary infections to which the patients are susceptible. Recently, three groups of PIDs have been found to affect immunity against primary infections without affecting immunity against secondary infections. Such disorders are characterized by the infectious phenotypes which usually include a single infectious episode, without the phenomenon of recurrence of infections. These are due to inborn mutations of IL12B and IL12RB1 (susceptible to infections by mycobacteria), IRAK4 and MYD88 (susceptible to infections by pyogenic bacteria, such as Streptococcus pneumonaie), and UNC93B1 and TLR3 (susceptible to infections by herpes simplex virus-1). Patients carrying these mutations have fatal infections during their childhood and show a remarkable improvement during adulthood, provided the initial infections are controlled by medical treatment {Bousfiha, 2010 }.

Patients with recessive mutations in IL12B or IL12RB1 have mendelian susceptibility to mycobacterial disease (MSMD) because of impairment of the IL-12 dependent production of IFN-γ. In these patients, mycobacteria such as BCG or Environmental mycobacteria (EM), cause mycobacterial diseases only once, typically during childhood. In two international studies on 38 and 141 patients with mutations in IL12B and IL12RB1 respectively, about 15% of the patients showed recurrence of mycobacterial infections, possibly due to reactivation of the initial mycobacterial pathogen due to improper treatment. Hence it appears that IL-12 is crucial for protective immunity to primary infection by BCG or EM, but has no role in immunity against secondary infections {Altare, 1998}.

Patients with mutations in IRAK4 or MYD88 are susceptible to infections caused by pyogenic bacteria.  In these patients, mendelian predisposition to infection is seen. This predisposition is due to impairment of inflammation. Both IRAK-4 and MyD88 deficiencies lead to defective TLR (except TLR3) and IL-1R (mainly IL-1, IL-18, and IL-33) signaling pathways (TIR). Invasive bacterial diseases, especially meningitis and septicemia, are caused by S. pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella enteritidis, and Shigellasonnei. Non-invasive bacterial disease is caused by S. aureus, P. aeruginosa and S. pneumoniae. Invasive bacterial infections occur in childhood and no infection is seen after the age of 14 years. This proves that TLR-mediated immunity is compensated by antibody responses to antigens. This disorder is linked with impaired immunity to primary infection by a set of pyogenic bacteria, mainly Streptococcus pneumoniae {Picard, 2003}. 

Patients with mutations in UNC93B1 and TLR3 are susceptible to infections by Herpes simplex virsus-1(HSV-1) and suffer from herpes simplex encephalitis (HSE) during childhood.  HSE is the most commonly occurring sporadic viral encephalitis, affecting even healthy children who are normally resistant to other infectious pathogens. Recurrences have been reported in lower than 10% of the total number of cases. Patients with autosomal recessive UNC-93B or autosomal dominant TLR3 deficiency develop HSE due to production of defective anti-viral interferons (IFNs) in their central nervous system (CNS) {De Tiège, 2008}. A study on skin derived fibroblasts showed the elimination of TLR3-dependent production of IFNs in the central nervous system. The enhanced viral replication and cell apoptosis could be treated with recombinant IFN-α. This study demonstrated that TLR3 dependent production of anti-viral IFNs is necessary for immunity against HSV-1 in the case of primary infection.

Studies on these new PID's demonstrate that infectious diseases that occur only once in childhood, are due to inborn errors in a single gene.  Thus, these new PID's may be seen as a paradigm shift in PID as they are associated only with primary infections and not with secondary infections.


Primary immunodeficiency diseases are of high importance for research as they are genetic disorders that affect both the innate and adaptive immune system. Studies on patient samples and animal models of these diseases have contributed to a better understanding of the development and functioning of the immune system. In addition, developments in the field of immunology, molecular biology, genetics and stem cell technology together could help to treat or even prevent PIDs. PIDs can be treated effectively if the occurrence is diagnosed at an early stage of disease as in many cases late diagnosis is detrimental. For example, Btk, which is associated with the B-cell disorder, is seen to be expressed in most haematopoietic stem cells, which could be exploited by stem cell technologists for the development of new gene and cell therapies to treat this disease.