-
Journal of Autoimmunity May 2023Genetic deficiencies of early components of the classical complement activation pathway (especially C1q, r, s, and C4) are the strongest monogenic causal factors for the... (Review)
Review
Genetic deficiencies of early components of the classical complement activation pathway (especially C1q, r, s, and C4) are the strongest monogenic causal factors for the prototypic autoimmune disease systemic lupus erythematosus (SLE), but their prevalence is extremely rare. In contrast, isotype genetic deficiency of C4A and acquired deficiency of C1q by autoantibodies are frequent among patients with SLE. Here we review the genetic basis of complement deficiencies in autoimmune disease, discuss the complex genetic diversity seen in complement C4 and its association with autoimmune disease, provide guidance as to when clinicians should suspect and test for complement deficiencies, and outline the current understanding of the mechanisms relating complement deficiencies to autoimmunity. We focus primarily on SLE, as the role of complement in SLE is well-established, but will also discuss other informative diseases such as inflammatory arthritis and myositis.
Topics: Humans; Complement C1q; Autoimmune Diseases; Complement System Proteins; Lupus Erythematosus, Systemic; Hereditary Complement Deficiency Diseases; Complement C4; Complement C4a
PubMed: 36535812
DOI: 10.1016/j.jaut.2022.102979 -
Arthritis & Rheumatology (Hoboken, N.J.) Jan 2024The role of complement in human autoimmune, inflammatory, and infectious diseases is reviewed, focusing on clinical applicability. A typical case is presented in which... (Review)
Review
The role of complement in human autoimmune, inflammatory, and infectious diseases is reviewed, focusing on clinical applicability. A typical case is presented in which serum testing for C3 and C4 is performed to help assess a syndrome with a broad differential diagnosis. The review includes a discussion of complement deficiency states, consumption of complement by diseases characterized by immune-complex formation and deposition, usefulness and interpretation of laboratory tests for complement, and development of drugs targeting specific components of the complement pathway for a growing number of indications.
Topics: Humans; Complement C4; Complement C3; Complement System Proteins; Syndrome
PubMed: 37551641
DOI: 10.1002/art.42671 -
Nature Feb 2016Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in...
Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
Topics: Alleles; Amino Acid Sequence; Animals; Axons; Base Sequence; Brain; Complement C4; Complement Pathway, Classical; Dendrites; Gene Dosage; Gene Expression Regulation; Genetic Predisposition to Disease; Genetic Variation; Haplotypes; Humans; Major Histocompatibility Complex; Mice; Models, Animal; Neuronal Plasticity; Polymorphism, Single Nucleotide; RNA, Messenger; Risk Factors; Schizophrenia; Synapses
PubMed: 26814963
DOI: 10.1038/nature16549 -
Allergy and Asthma Proceedings Nov 2019Hereditary angioedema (HAE) is an autosomal dominant disorder defined by a deficiency of functional C1 esterase inhibitor (C1-INH). Acquired angioedema is due to either... (Review)
Review
Hereditary angioedema (HAE) is an autosomal dominant disorder defined by a deficiency of functional C1 esterase inhibitor (C1-INH). Acquired angioedema is due to either consumption (type 1) or inactivation (type 2) of CI-INH. Both HAE and acquired angioedema can be life-threatening. Of the three types of HAE, type 1 is most common, occurring in approximately 85% of patients and characterized by decreased production of C1-INH, which results in reduced functional activity to 5-40% of normal. Type 2 occurs in 15% of cases; C1-INH is detectable in normal or elevated quantities but is dysfunctional. Also, HAE with normal CI-INH (previously called type 3 HAE) is rare and characterized by normal complement studies. Specific genetic mutations have been linked to factor XII, angiopoietin-1, and plasminogen gene. Patients with unknown mutations are classified as unknown. The screening test for types 1 and 2 is complement component C4, which is low to absent at times of angioedema and during quiescent periods. A useful test to differentiate HAE from acquired angioedema is C1q protein, which is normal in HAE and low in acquired angioedema. The management of HAE has been transformed with the advent of disease-specific therapies. On-demand therapy options include plasma and recombinant C1-INH for intravenous infusion; ecallantide, an inhibitor of kallikrein; and icatibant, a bradykinin β₂ receptor antagonist, both administered subcutaneously. For long-term prophylaxis, intravenous or subcutaneous C1-INH enzyme replacement and lanadelumab, a monoclonal antibody against kallikrein that is administered subcutaneously, are effective agents.
Topics: Angioedema; Angioedemas, Hereditary; Complement C1 Inhibitor Protein; Complement C4; Diagnosis, Differential; Humans; Mutation
PubMed: 31690390
DOI: 10.2500/aap.2019.40.4267 -
Nature Neuroscience Feb 2021The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an...
The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how C4A shapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4, human C4A and/or C4B. Human C4A bound synapses more efficiently than C4B. C4A (but not C4B) rescued the visual system synaptic refinement deficits of C4 knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing C4A in mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia.
Topics: Animals; Behavior, Animal; Complement C4; Dendritic Spines; Depression; Female; Gene Dosage; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microglia; Nerve Net; Psychomotor Performance; Schizophrenia; Schizophrenic Psychology; Synapses; Synaptosomes
PubMed: 33353966
DOI: 10.1038/s41593-020-00763-8 -
Frontiers in Immunology 2021Complement C4, a key molecule in the complement system that is one of chief constituents of innate immunity for immediate recognition and elimination of invading... (Review)
Review
Complement C4, a key molecule in the complement system that is one of chief constituents of innate immunity for immediate recognition and elimination of invading microbes, plays an essential role for the functions of both classical (CP) and lectin (LP) complement pathways. Complement C4 is the most polymorphic protein in complement system. A plethora of research data demonstrated that individuals with C4 deficiency are prone to microbial infections and autoimmune disorders. In this review, we will discuss the diversity of complement C4 proteins and its genetic structures. In addition, the current development of the regulation of complement C4 activation and its activation derivatives will be reviewed. Moreover, the review will provide the updates on the molecule interactions of complement C4 under the circumstances of bacterial and viral infections, as well as autoimmune diseases. Lastly, more evidence will be presented to support the paradigm that links microbial infections and autoimmune disorders under the condition of the deficiency of complement C4. We provide such an updated overview that would shed light on current research of complement C4. The newly identified targets of molecular interaction will not only lead to novel hypotheses on the study of complement C4 but also assist to propose new strategies for targeting microbial infections, as well as autoimmune disorders.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Communicable Diseases; Complement Activation; Complement C4; Host-Pathogen Interactions; Humans; Signal Transduction
PubMed: 34335607
DOI: 10.3389/fimmu.2021.694928 -
Arthritis & Rheumatology (Hoboken, N.J.) Aug 2022
Topics: Autoimmunity; Complement C4; Major Histocompatibility Complex
PubMed: 35315246
DOI: 10.1002/art.42119 -
Current Diabetes Reviews 2019Increased systemic inflammation plays a significant role in the development of adult cardiometabolic diseases such as insulin resistance, dyslipidemia, atherosclerosis,... (Review)
Review
INTRODUCTION
Increased systemic inflammation plays a significant role in the development of adult cardiometabolic diseases such as insulin resistance, dyslipidemia, atherosclerosis, and hypertension. The complement system is a part of the innate immune system and plays a key role in the regulation of inflammation. Of particular importance is the activation of complement components C3 and C4. C3 is produced primarily by the liver but is also produced in adipocytes, macrophages and endothelial cells, all of which are present in adipose tissues. Dietary fat and chylomicrons stimulate C3 production. Adipocytes in addition to producing C3 also have receptors for activated C3 and other complement components and thus also respond to as well as produce a target for complement. C3adesArg, also known as acylation stimulation factor, increases adipocyte triglyceride synthesis and release. These physiological effects play a significant role in the development of metabolic syndrome. Epidemiologically, obese adults and non-obese adults with cardiometabolic disease who are not obese have been shown to have increased complement levels. C4 levels also correlate with body mass index. Genetically, specific C3 polymorphisms have been shown to predict future cardiovascular events and. D decreased C4 long gene copy number is associated with increased longevity.
CONCLUSION
Future research is clearly needed to clarify the role of complement in the development of cardiovascular disease and mechanisms for its action. The complement system may provide a new area for intervention in the prevention of cardiometabolic diseases.
Topics: Adult; Complement C3; Complement C4; Complement Pathway, Classical; Humans; Insulin Resistance; Metabolic Syndrome; Obesity
PubMed: 29663892
DOI: 10.2174/1573399814666180417122030 -
Annals of Human Genetics Sep 2018A number of important findings have recently emerged relevant to identifying genetic risk factors for schizophrenia. Findings using common variants point towards gene... (Review)
Review
A number of important findings have recently emerged relevant to identifying genetic risk factors for schizophrenia. Findings using common variants point towards gene sets of interest and also demonstrate an overlap with other psychiatric and nonpsychiatric disorders. Imputation of variants of the gene for complement component 4 (C4) from GWAS data has shown that the predicted expression of the C4A product is associated with schizophrenia risk. Very rare variants disrupting SETD1A, RBM12 or NRXN1 have a large effect on risk. Other rare, damaging variants are enriched in genes that are loss of function intolerant and/or whose products localise to the synapse. These and particular copy number variants can result in increased risk of schizophrenia but also of other neurodevelopmental disorders. The findings for C4 and NRXN1 may be especially helpful for elucidating the biological mechanisms that can lead to disease.
Topics: Calcium-Binding Proteins; Cell Adhesion Molecules, Neuronal; Complement C4; DNA Copy Number Variations; Genome-Wide Association Study; Histone-Lysine N-Methyltransferase; Humans; Nerve Tissue Proteins; Neural Cell Adhesion Molecules; RNA-Binding Proteins; Risk Factors; Schizophrenia
PubMed: 29923609
DOI: 10.1111/ahg.12259 -
Lupus Nov 2019Prognosis of pregnancies in women with antiphospholipid syndrome has dramatically improved over the past two decades using conventional treatment with low molecular...
Prognosis of pregnancies in women with antiphospholipid syndrome has dramatically improved over the past two decades using conventional treatment with low molecular weight heparin and low-dose aspirin. However, despite this regimen, 10-15% of antiphospholipid syndrome patients experience pregnancy losses. Several studies have been performed in order to identify risk factors predictive of complications. Thrombosis has been generally accepted as the key pathogenetic mechanism underlying pregnancy morbidity. However, the thrombogenic state alone is not able to explain all the different mechanisms leading to pregnancy failure. In fact, emerging evidence shows that complement pathway could play an important role in mediating clinical events in antiphospholipid syndrome. However, the exact mechanism through which complement mediates antiphospholipid syndrome complications remains unknown. Low complement levels (C3 and C4) are associated with poor pregnancy outcome in women with antiphospholipid syndrome in different studies. Hypocomplementemia could be indicated as an early predictor of adverse pregnancy outcome, available at the beginning of pregnancy for starting, if necessary, additional treatment to conventional therapy. However, future studies need to better understand the impact of low complement level on antiphospholipid syndrome pregnancy outcome.
Topics: Anticoagulants; Antiphospholipid Syndrome; Complement Activation; Complement C3; Complement C4; Female; Humans; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prognosis; Risk Factors; Thrombosis
PubMed: 31623520
DOI: 10.1177/0961203319882507