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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 -
Current Rheumatology Reports Feb 2021Complement activation is a key event in the pathogenesis of tissue inflammation and injury in systemic lupus erythematosus (SLE). This review is aimed at comparing the... (Review)
Review
PURPOSE OF REVIEW
Complement activation is a key event in the pathogenesis of tissue inflammation and injury in systemic lupus erythematosus (SLE). This review is aimed at comparing the usefulness of measurement of complement proteins in serum/plasma (C3, C4) to complement activation (split) products in plasma and on circulating blood cells for SLE diagnosis, disease monitoring, and prognosis.
RECENT FINDINGS
Complement split products, C3dg, iC3b, and C4d, are elevated in SLE, and C3dg/C3 and iC3b/C3 ratios correlate with active SLE. C4d also is higher in patients with lupus nephritis. An elevated level of the alternative pathway split product, Bb, in early lupus pregnancy is a predictor of adverse outcomes in SLE patients with antiphospholipid antibodies. Elevated levels of cell-bound complement activation products (CB-CAPs), namely, B cell-bound C4d (BC4d) and erythrocyte-bound C4d (EC4d), within a multiparameter assay panel, may predict transition to SLE more than other lupus biomarkers. EC4d better correlates with lupus disease activity than low plasma complement levels. Elevated platelet-bound C4d (PC4d) correlates with thrombosis in SLE. Both EC4d and PC4d are increased in primary and secondary anti-phospholipid syndrome, and anti-beta2glycoproteinI antibodies may directly activate the complement system. Abnormal levels of plasma complement split products and CB-CAPs support complement activation as an important pathogenetic mechanism in SLE and the antiphospholipid syndromes. These tests show promise for the diagnosis of SLE and monitoring of disease activity.
Topics: Antiphospholipid Syndrome; Biomarkers; Complement Activation; Complement System Proteins; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis
PubMed: 33569681
DOI: 10.1007/s11926-021-00984-1 -
Biomolecules Feb 2023Systemic lupus erythematosus (SLE) is a disease of immune complex deposition; therefore, complement plays a vital role in the pathogenesis of SLE. In general, complement... (Review)
Review
Systemic lupus erythematosus (SLE) is a disease of immune complex deposition; therefore, complement plays a vital role in the pathogenesis of SLE. In general, complement levels in blood and complement deposition in histological tests are used for the management of SLE. Thus, the evaluation of complement status can be useful in the diagnosis of SLE, assessment of disease activity, and prediction of treatment response and prognosis. In addition, novel complement biomarkers, such as split products and cell-bound complement activation products, are considered to be more sensitive than traditional complement markers, such as serum C3 and C4 levels and total complement activity (CH50), which become more widely used. In this review, we report the complement testing in the management of SLE over the last decade and summarize their utility.
Topics: Humans; Lupus Erythematosus, Systemic; Complement System Proteins; Biomarkers
PubMed: 36830735
DOI: 10.3390/biom13020367 -
International Journal of Molecular... Aug 2021Age-related macular degeneration (AMD), one of the leading causes of blindness worldwide, causes personal suffering and high socioeconomic costs. While there has been...
Age-related macular degeneration (AMD), one of the leading causes of blindness worldwide, causes personal suffering and high socioeconomic costs. While there has been progress in the treatments for the neovascular form of AMD, no therapy is yet available for the more common dry form, also known as geographic atrophy. We analysed the retinal tissue in a mouse model of retinal degeneration caused by sodium iodate (NaIO)-induced retinal pigment epithelium (RPE) atrophy to understand the underlying pathology. RNA sequencing (RNA-seq), qRT-PCR, Western blot, immunohistochemistry of the retinas and multiplex ELISA of the mouse serum were applied to find the pathways involved in the degeneration. NaIO caused patchy RPE loss and thinning of the photoreceptor layer. This was accompanied by the increased retinal expression of complement components , , and . C1s, C3, CFH and CFB were complement proteins, with enhanced deposition at day 3. C4 was upregulated in retinal degeneration at day 10. Consistently, the transcript levels of proinflammatory , , , , and were increased in the retinas of NaIO mice, but mRNA was reduced. Macrophages, microglia and gliotic Müller cells could be a cellular source for local retinal inflammatory changes in the NaIO retina. Systemic complement and cytokines/chemokines remained unaltered in this model of NaIO-dependent retinal degeneration. In conclusion, systemically administered NaIO promotes degenerative and inflammatory processes in the retina, which can mimic the hallmarks of geographic atrophy.
Topics: Animals; Apoptosis; Complement System Proteins; Disease Models, Animal; Disease Susceptibility; Fluorescent Antibody Technique; Gene Expression Regulation; Immunity, Innate; Immunohistochemistry; Iodates; Mice; Retinal Degeneration
PubMed: 34502128
DOI: 10.3390/ijms22179218 -
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 -
Journal of Ayub Medical College,... 2023We present the case of a 30-year-old woman who presented with 8-month history of intermittent fever, joint pains with morning stiffness, recurrent oral ulcers,...
We present the case of a 30-year-old woman who presented with 8-month history of intermittent fever, joint pains with morning stiffness, recurrent oral ulcers, photosensitivity, weight loss and hair fall. For the last 2 months, she had developed a dry cough with progressive shortening of breath. On examination, a cachexic lady with malar hyperpigmentation, alopecia, pallor, nail dystrophy and erythema over her hands and feet were noted. There were multiple punched-out skin ulcers of variable size over legs, arms and abdomen usually round in shape with well-defined even wound margins and scant serous discharge. Musculoskeletal examination revealed synovitis of both elbows and a few metacarpophalangeal and proximal interphalangeal joints. Chest X-ray and HRCT showed bilateral ground-glass opacification. Anti-Nuclear Antibody (ANA) was positive, 1:320, homogenous nuclear pattern. Anti-Ro antibody was highly positive and serum complement (C3, C4) levels were reduced. She was diagnosed with Lupus Vasculitis and started on steroids, mycophenolate mofetil and hydroxychloroquine.
Topics: Humans; Female; Adult; Mycophenolic Acid; Fever; Arthralgia; Vasculitis
PubMed: 38404096
DOI: 10.55519/JAMC-03-10849 -
Frontiers in Immunology 2022Graves' ophthalmopathy (GO), the most frequent extrathyroidal manifestation of Graves' disease (GD), can lead to a significant decline in the quality of life in...
Graves' ophthalmopathy (GO), the most frequent extrathyroidal manifestation of Graves' disease (GD), can lead to a significant decline in the quality of life in patients. Exosomes, which contain proteins, lipids and DNA, play important roles in the pathological processes of various diseases. However, their roles in Graves' ophthalmopathy are still unclear. We aimed to isolate exosomes and analyze the different exosomal proteins. Tear fluids were collected from twenty-four GO patients, twenty-four GD patients and sixteen control subjects. The numbers of tear exosomes were assayed using nanoparticle tracking analysis. A Luminex 200 kit and ELISA kit were used to confirm the different cytokine concentrations in serum. Extraocular muscle from GO patients and controls was extracted, and western blotting was used to assay the levels of Caspase-3 and complement C4A. Our study demonstrated that the number of tear exosomes differ from GD patients and control. The expression levels of cytokines, including IL-1 and IL-18, were significantly increased in the tear exosomes and serum from GO patients compared with GD patients and controls. The levels of the exosomal proteins Caspase-3, complement C4A and APOA-IV were significantly increased in GO patients compared to GD patients and controls. Orbital fibroblasts from GO patients showed significantly higher levels of Caspase-3 and complement C4A than those from controls. The levels of serum APOA-IV in GO patients were significantly higher than those in GD patients and controls. Specific proteins showed elevated expression in tear exosomes from GO patients, indicating that they may play important roles in GO pathogenesis.
Topics: Humans; Biomarkers; Caspase 3; Complement C4a; Cytokines; Graves Ophthalmopathy; Quality of Life; Tears; Exosomes
PubMed: 36561758
DOI: 10.3389/fimmu.2022.1088606 -
Frontiers in Immunology 2022Proteins destined for secretion - after removal of the signal sequence - often undergo further proteolytic processing by proprotein convertases (PCs). Prohormones are... (Review)
Review
Proteins destined for secretion - after removal of the signal sequence - often undergo further proteolytic processing by proprotein convertases (PCs). Prohormones are typically processed in the regulated secretory pathway, while most plasma proteins travel though the constitutive pathway. The complement system is a major proteolytic cascade in the blood, serving as a first line of defense against microbes and also contributing to the immune homeostasis. Several complement components, namely C3, C4, C5 and factor I (FI), are multi-chain proteins that are apparently processed by PCs intracellularly. Cleavage occurs at consecutive basic residues and probably also involves the action of carboxypeptidases. The most likely candidate for the intracellular processing of complement proteins is furin, however, because of the overlapping specificities of basic amino acid residue-specific proprotein convertases, other PCs might be involved. To our surprise, we have recently discovered that processing of another complement protein, mannan-binding lectin-associated serine protease-3 (MASP-3) occurs in the blood by PCSK6 (PACE4). A similar mechanism had been described for the membrane protease corin, which is also activated extracellularly by PCSK6. In this review we intend to point out that the proper functioning of the complement system intimately depends on the action of proprotein convertases. In addition to the non-enzymatic components (C3, C4, C5), two constitutively active complement proteases are directly activated by PCs either intracellularly (FI), or extracellularly (MASP-3), moreover indirectly, through the constitutive activation of pro-factor D by MASP-3, the activity of the alternative pathway also depends on a PC present in the blood.
Topics: Mannose-Binding Protein-Associated Serine Proteases; Proprotein Convertases; Proteolysis
PubMed: 35874789
DOI: 10.3389/fimmu.2022.958121 -
Nature Cancer Feb 2021Complement has emerged as a component of tumor promoting inflammation. We conducted a systematic assessment of the role of complement activation and effector pathways in...
Complement has emerged as a component of tumor promoting inflammation. We conducted a systematic assessment of the role of complement activation and effector pathways in sarcomas. , and mice showed reduced susceptibility to 3-methylcholanthrene sarcomagenesis and transplanted sarcomas, whereas C1q and factor B deficiency had marginal effects. Complement 3a receptor (C3aR), but not C5aR1 and C5aR2, deficiency mirrored the phenotype of mice. C3 and C3aR deficiency were associated with reduced accumulation and functional skewing of tumor-associated macrophages, increased T cell activation and response to anti-PD-1 therapy. Transcriptional profiling of sarcoma infiltrating macrophages and monocytes revealed the enrichment of MHC II-dependent antigen presentation pathway in C3-deficient cells. In patients, C3aR expression correlated with a macrophage population signature and C3 deficiency-associated signatures predicted better clinical outcome. These results suggest that the lectin pathway and C3a/C3aR axis are key components of complement and macrophage-mediated sarcoma promotion and immunosuppression.
Topics: Animals; Complement Activation; Humans; Immunosuppression Therapy; Lectins; Mice; Monocytes; Receptor, Anaphylatoxin C5a; Receptors, Complement; Sarcoma
PubMed: 34505065
DOI: 10.1038/s43018-021-00173-0