PID - deficiency of complement

The term "immunodeficiency diseases" (synonym: immunodeficiency syndromes) covers various diseases of the immune system that are characterized by a temporary or irreversible disturbance of the immune function. Congenital or primary immunodeficiencies (PID) are diseases in which the immunodeficiency is congenital, occurs in families and/or can be inherited. The PID group is contrasted with diseases and referred to by the generic term "secondary or acquiredimmunodeficiencies", in which the immunodeficiency has been acquired. The best-known example of this is AIDS (acquired immune deficiency syndrome).

One of the developmentally oldest components of the immune system is the complement system. Strictly regulated, similar to a coagulation cascade, especially encapsulated germs (e.g. meningococci) can be perforated and killed by complement factors, among others. Complement is also involved in the regulation of immune responses and the elimination of immune complexes. This explains the favored occurrence of Systemic Lupus Erythematosus or other autoimmune diseases in the case of defects of the immune system. Defects of the complement cascade C1 to C9 are described for all proteins with immunological disorders. In the lectin activation pathway, there are described deficiencies of the Mann-binding lectin (MBL), among others.

Defects of different regulatory proteins within the complement activation pathway lead to very different diseases. These include hereditary angioedema and atypical hemolytic uremic syndrome (HUS).

Mutations in the serum complement subcomponents

• C1q defect (C1QA defect): autosomal recessive mutation in the C1QA gene (C1QA stands for "Complement C1q A Chain") which is located on chromosome 1p36.12. The gene encodes the A-chain polypeptide of the serum complement subcomponent C1q, which together with C1r and C1s forms the first component of the serum complement system. Mutations in this gene lead to C1q deficiency/deficiency(C1q deficiency, familial; OMIM: 613652) and is associated with systemic lupus erythematosus as well as glomerulonephritis. Furthermore, there is an increased propensity for infections with encapsulated pathogens/impaired elimination of apoptotic cells.
• C1q defect (C1QB): autosomal recessive mutation in the C1QB gene (C1QB stands for "complement C1q B chain") located on chromosome 1p36.12. The gene encodes the B-chain polypeptide of the serum complement subcomponent C1q, which together with C1r and C1s forms the first component of the serum complement system. Mutations in this gene lead to C1q deficiency. This defect is associated with lupus erythematosus and glomerulonephritis. Furthermore, increased propensity for infections with encapsulated pathogens. Impaired elimination of apoptotic cells.
• C1q defect (C1QC): AR/mutation in the C1QC gene(C1QC stands for "Complement C1q C Chain") which is located on chromosome 1p36.12. The C1QC gene encodes the B-chain polypeptide of the serum complement subcomponent C1q, which together with C1r and C1s forms the first component of the serum complement system(C1q deficiency, familial; OMIM: 613652) /mutations in this gene lead to C1q deficiency/ this defect is associated with lupus erythematosus and glomerulonephritis/ furthermore increased tendency to infections with encapsulated pathogens/ impaired elimination of apoptotic cells.
• C1r defect: AR/mutation in the C1R gene (C1R stands for "complement C1r") which is located on chromosome 12p13.31. Mutations in this gene lead to the syndrome of "complement C1s deficiency" to systemic lupus erythematosus and to an SLE-like (with increased tendency to infections with encapsulated pathogens) syndrome/ other diseases associated with C1R: periodontal Ehlers-Danlos syndrome.
• C1s defect: the C1S gene (C1S stands for "Complement C1S") is located on chromosome 12p13.31. AR/mutations in this gene lead to systemic lupus erythematosus and a clinical picture with SLE-like symptoms, an increased tendency to infections with encapsulated pathogens. Other diseases associated with C1S include periodontal Ehlers-Danlos syndrome. Note: The C1s B chain is a serine protease that, together with C1q and C1r, forms the complement component C1/this is the first component of the classical pathway of the complement system. Dei complement cascade can thus be activated. C1r activates C1s, so that this in turn can activate C2 and C4.
• C2 defect: AR/mutation in the C2 gene (C2 stands for "complement 2")/located at chromosome 6p21.33/mutation of the complement component leads to SLE-like clinical pictures/to vasculitis, polymyositis as well as to an increased tendency to infections with encapsulated pathogens.
• C3 defect (see below C3 deficiency syndrome): AR/LOF mutation in the C3 gene (C3 stands for complement 3) which is located on chromosome 19p13.3/the LOF mutation in this gene leads to recurrent purulent infections, glomerulonephritis and an atypical HUS syndrome(hemolytic uremic syndrome). CH50 and AP50 not measurable!
• C3 defect: AD/ GOF mutation in the C3 gene (C3- stands for complement C3) which is located on chromosome 19p13.3. The mutation leads to increased C3 activation and atypical HUS syndrome(hemolytic uremic syndrome)/ Note: Complement component C3 plays a central role in the activation of the complement system. Its activation is required for both the classical and alternative complement activation pathways. The encoded preprotein is proteolytically processed to generate alpha and beta subunits that form the mature protein, which is then further processed to generate numerous peptide products. The C3a peptide, is also known as C3a anaphylatoxin, modulates inflammation and has antimicrobial activity.
• C3 Dysfunction: AR/ p. I734T mutation in the C3 gene (C3- stands for complement C3) which is located on chromosome 19p13.3. The mutation leads to C3 glomerulopathy.
• C4 defe ct (complete C4 defect/C4A + C4B ; see below C4a deficiency syndrome): AR/ mutations in the C4A + C4B genes result in partial defects in the C4a or C4b complement fractions. Clinically, SLE-like symptoms, infections with encapsulated pathogens are found. Complete C4 defect requires biallelic mutations/deletions/conversions at C4A and C4B.
• C5 defe ct: AR/ mutation in the C5 gene (C5 stands for complement 5) which is located on chromosome 9q33.2. The mutation leads to an increased tendency to Neisseria infections, further to SLE. Leiner's disease is also associated with a C5 defect. CH50 and AP50 not measurable.
• C6 defect: AR/ mutation in the C6 gene (C6 stands for complement 6) which is located on chromosome 5p13. The mutation leads to an increased tendency to contract Neisseria infections. CH50 and AP50 not measurable.
• C8alpha defect: AR/ mutation in the C8A gene (C8A stands for complement C8 alpha chain) located on chromosome 1p32.2. The mutation leads to (dysfunction in the membrane attack complex-MAC) increased propensity to contract Neisseria infections. CH50 and AP50 not measurable.
• C8beta defect: AR/ mutation in the C8B gene (C8 beta stands for complement C8 beta chain) which is located on chromosome 1p32.2. The mutation leads to dysfunction in the membrane attack complex-MAC and thus to an increased tendency to contract Neisseria infections (especially meninogococci) . CH50 and AP50 not measurable.
• C8gamma defect: AR/ mutation in the C8G gene (C8gamma stands for complement C8 gamma chain) located on chromosome 9q34.3. The mutation leads to an increased tendency to contract Neisseria infections(Immunodeficiency Due to a Late Component of Complement Deficiency). CH50 and AP50 not measurable.
• C9 defect: AR/mutation in the C9 gene (C9 stands for Complement 9) which is located on chromosome 5p13.1. The mutation leads to a slightly increased tendency to contract Neisseria infections. A C9 defect could be associated with dermatomyositis. CH50 and AP50 not measurable.
• MASP2 deficiency: AR/ mutation in the MASP2 gene (MASP2 stands for "Mannose-Binding Protein-Associated Serine Protease 2") which is located on chromosome 1p36.22. The MASP2 gene encodes a member of the peptidase S1 family of serine proteases. The encoded preprotein undergoes proteolytic processing to generate A and B chains that heterodimerize to form the mature protease. The encoded protease cleaves complement components C2 and C4 to generate C3 convertase in the lectin pathway of the complement system. It also plays a role in the coagulation cascade by cleaving prothrombin to thrombin. Mutation in this gene leads to deficient activation of the lectin pathway and clinically to purulent infections and inflammatory pulmonary disease as well as autoimmunity.
• Ficolin-3 defect: AR/ mutation in the FCN3 gene (FCN3 stands for "Collagen/Fibrinogen Domain-Containing Protein 3") located on chromosome 1p36.11. The protein encoded by this gene is a thermolabile beta-2 macroglycoprotein belonging to the ficolin/opsonin p35 lectin family. The protein, in conjunction with MASPs and sMAP, can activate the complement pathway, contributing to host defense by activating the lectin pathway. The mutation leads clinically to recurrent infections especially of the respiratory tract to abscess formation. Furthermore: disturbance of the formation of pneumococcal antibodies; 8-fold increased tendency to develop SLE.
• Factor B defect (see below CFB gene): AD/ GOF mutation in the CFB gene (CFB stands for "Complement Factor B") which is located on chromosome 6p21.33, in the region of the major histocompatibility complex (MHC) class III. This cluster includes several genes involved in the regulation of the immune response/ The CFB gene encodes complement factor B, a component of the alternative pathway of complement activation. Factor B circulates in the blood as a single-chain polypeptide. Polymorphisms in this gene are associated with a lower risk of age-related macular degeneration. The autosomal dominant GOF mutation leads to an increase in the activity of AP50. Clinically, the mutation is associated with atypical HUS syndrome. Other mutations result in activity decreases of AP50. Clinically, to an increased tendency to infections with encapsulated bacteria(CH50 normal, AP50 decreased).
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• C1 Inhibitor Defects
• C1 inhibitor homozygosity (very rare): AR/mutations in the SERPING1 gene (SERPING1 stands for "Serpin Peptidase Inhibitor, Clade G (C1 Inhibitor), Member 1") which is located on chromosome 11q12.1 result in a mild form of hereditary angioedema (HAE). Type I = antigen deficiency, type II = dysfunction.
• C1 inhibitor heterozygosity
• HAE with normal C1 INH (formerly HAE type III): Partial mutations in coagulation factor XII (F XII HAE), ANGPT1 (ANG-1-HAE), plasminogen (PLG HAE).
• Factor D defect: autosomal recessive mutations in the CFD gene (CFD stands for "Complement Factor D") located on chromosome 19p13.3 lead to immunodeficiency with an increased tendency to Neisseria infections.
• Properdin defe ct: X-linked recessive mutations in the CFP gene (CFP stands for "Complement Factor Properdin") located on chromosome Xp11.23 lead to Properdin deficiency and to an immunodeficiency with an increased tendency to Neisseria infections.
• Factor I defect: AR/ mutations in the CFI gene (CFI stands for " Complement Factor I) located on chromosome 4q25 lead to spontaneous activation of AP with C3 consumption. Clinically, recurrent bacterial infections including Neisseria infection occur. The CFI gene is further associated with HUS syndrome, with membranoproliferative glomerulonephritis and with preeclampsia.
• Factor H defect: Autosomal recessive/dominant mutations in the CFH gene (CFH stands for "Complement Factor H") located on chromosome 1q31.3/spontaneous activation of AP with C3 consumption/ clinically recurrent bacterial infections including neisseria infections. Mutations in the CFH gene are further associated with HUS syndrome as well as with membranoproliferative glomerulonephritis and with preeclampsia.
• Factor H related protein defect: Autosomal dominant/recessive mutations in CFHRP1-5 (Complement Factor H Related 1-5) genes localized in a cluster region on chromosome 1q31.3/ proteins bind C3b/ mutations in the genes are associated with atypical hemolytic uremic syndrome (HUS), with Neisseria infections. CH50 and AP50 normal.
• Thrombomodulin defect: AD/ mutations in the THBD gene (THBD stands for thrombomodulin) localized on chromosome 20p11.21 result in disorders of coagulation and complement regulation. Clinically, atypical hemolytic uremic syndrome is associated with these mutations. CH50 u. AP50 normal.
• COLEC11 defect: Autosomal recessive mutations in the COLEC11 gene (COLEC11 stands for "Collectin Subfamily Member 11") on chromosome 2p25.3. Mutations lead to immunodeficiencies. The COLEC11 gene encodes a member of the collectin family of C-type lectins that have collagen-like sequences and carbohydrate recognition domains. Collectins are secreted proteins that play an important role in the innate immune system by binding to carbohydrate antigens on microorganisms to facilitate their recognition and removal. The encoded protein binds to polysaccharides, preferring fucose and mannose. Diseases associated with COLEC11 (absence of type C lectin CLK1) include 3Mc syndrome 2. Absence of type C lectin CLK1 is associated with 3MC syndrome (facial dysmorphia, cleft formation, craniosynostosis, learning disability, genital, vesicorenal and limb malformations).
• CD46 defect: Autosomal dominant mutations in the CD46 gene, which encodes the MCP protein (MCP stands for "Membrane Cofactor Protein"), result in immunodeficiency. The MCP protein is involved in the cleavage of C3b and C4b. MCP mutation lead to increased susceptibility to infection, atypical hemolytic uremic syndrome and preeclampsia.
• CD59 defect: Autosomal recessive mutations in the CD59 gene encoding the "Membrane Attack Complex (MAC) Inhibition Factor" lead to immunodeficiency. MAC regulates the formation of the membrane attack complex. Mutations in this gene are associated with complement-mediated hemolysis as well as polyneuropathy.
• CD55 defect (CHAPEL disease): Autosomal recessive mutations in the CD55 gene lead to hyperactivation of complement at endothelia. Clinically, protein-losing enteropathy and an increased tendency to thrombosis are found.