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Immunodeficiency Diseases
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
The complement system comprises a tightly regulated pathway that recognizes biochemical divergence between self-structures from structural pathogen associated molecular patterns such as the lipopolysaccharide of gram-negative bacteria, mannose of fungi, ficolins of some gram-positive bacteria. This leads to activation of distinct early complement proteins, generation of convertases that converge on C3 giving rise to the anaphylatoxins C4a and C3a as well as C3b. Beside its opsonic function C3b functions as an enzyme in generating C5a, a chemoattractant for phagocytic cells. Collectively, the anaphylatoxins (C3a, C4a and C5a) mediate the vascular phase of inflammation while C5a recruits the phagocytic cells resulting in integrating the vascular and cellular phase of immune defenses and inflammation. Derangements in this cascade of activating and regulatory proteins leads to either failure of complement mediated defenses and hence recurrent or severe infections or auto activation of complement proteins leading to immune inflammation, defects in complement mediated clearance of apoptotic cells causing autoimmune diseases. Figure 29.2 summarizes the clinical picture as well as the laboratory evaluation of the complement system that leads to a definition of the specific complement protein deficiency.
The complement system in health and disease
Published in Gabriel Virella, Medical Immunology, 2019
The lectin pathway is initiated by target recognition through the binding of circulating lectins, such as plasma mannan-binding lectin (MBL) and Ficolins 1–3. These protein components belong to the collectin family, structurally resemble C1q, and are involved with the recognition of foreign organisms such as bacteria and virus. Mannan, a constituent of the polysaccharide capsules of many pathogenic fungi and yeasts (e.g., Cryptococcus neoformans and Candida albicans), is one of several polysaccharide substances to which MBL binds via Ca2+-dependent interactions, while bacterial lipoteichoic acid and peptidoglycan associate with serum Ficolins. In addition to carbohydrate motifs of microorganisms, MBL can bind to glycoproteins on the envelope of several types of viruses. The activation of the lectin pathway does not involve antigen-antibody interactions. Like the alternative complement pathway, the lectin pathway is an innate system designed to activate the complement system independently of specific antibodies, and as such requires no adaptive immune system help. Both mannan-binding lectin and ficolins are acute-phase reactants, meaning that their concentration increases during infection and inflammation. Both types of lectins stay associated with serum serine proteases, and upon binding initiation proceeds through the activations of processes mediated by MBL-associated serine proteases (MASPs) such as MASP-1, MASP-2, and MASP-3. These proteases form a tetrameric complex similar to the one formed by C1r and C1s of the classical pathway, and MASP-2 subsequently cleaves C4 and C2, and then subsequently C3 in the same manner as that of the classical pathway (Figure 9.3).
The pathophysiology of mitral stenosis
Published in Neeraj Parakh, Ravi S. Math, Vivek Chaturvedi, Mitral Stenosis, 2018
Sudheer Arava, Kusuma Harisha, Ruma Ray
Genetic susceptibility:28 Only a small percentage of individuals with untreated streptococcal sore throat develop rheumatic fever and only a subset of these proceed with persistent inflammation and chronic RHD, suggesting a genetic susceptibility (see Flowchart 4.1). Studies have shown that the risk of acute rheumatic fever is six times higher in monozygotic twins when compared with that of dizygotic twins. Different Human leucocyte antigen (HLA) class II antigens have been found to be associated with several populations and HLA-DR 7 is the antigen most frequently associated with RHD. This may indicate the association of different strains of streptococcus in different regions of the world. This evidence has led researchers to study various susceptible gene associations in RHD patients. Some authors have documented that the majority of these genes were found to be involved in the regulation of the immune system. Major proteins involved in the innate immunity protection response are mannose-binding lectin protein (MBL), the family of toll-like receptors (TLR), and ficolins. MBL and ficolins are pattern recognizing proteins that are helpful in identifying the surface proteins of the pathogens for further processing. MBL binds to N-acetylglucosamine (GlcNAc), the major immune-epitope of GAS cell wall carbohydrates. This protein has immunological similarities to the cardiac valve laminin. Ficolin-2 has shown to bind selectively to lipoteichoic acid, a cell wall constituent of GAS. TLRs play a key role in host immunity by mediating inflammatory mediators. TLR 2 interacts with bacterial lipoprotein, peptidoglycans, and lipoteichoic acid, which are the constituents of GAS cell wall. Polymorphisms are known to be associated with RHD. Some of the important known polymorphisms are cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism, signal transducer and activation of transcription (STAT) 3, STAT5b, IL-10, and IL-6. Transforming growth factor (TGF) beta is the key regulator of fibrosis and calcification.31
Macrophage polarization: an effective approach to targeted therapy of inflammatory bowel disease
Published in Expert Opinion on Therapeutic Targets, 2021
Yaoyao Du, Lan Rong, Yuanhua Cong, Lan Shen, Ning Zhang, Bing Wang
Ficolins (FCNs) are carbohydrate recognition proteins on pathogens, apoptotic cells, and necrotic cells and act as activators of the lectin complement pathway [127]. FCNs are closely related to pathogenic microbial infections, but their effects on IBD are rarely reported [128]. At present, the three FCNs found in humans are FCN-1, FCN-2, and FCN-3; the two FCNs identified in mice are FCN-A and FCN-B. Human FCN-2 and mouse FCN-A are very similar in structure, function, and biological level [129–131]. Interestingly, the levels of FCN-2 in the serum of IBD patients and FCN-A in the tissues of colitis mice were higher than those in the normal group, and FCN-A gene deletion can help alleviate colon inflammation and tissue damage in mice [132]. FCN-A/2 has been shown to inhibit M2 macrophage polarization: it can downregulate the expression levels of IL-10, Arg1, and CD206 and upregulate the expression levels of M1 phenotypic markers such as iNOS, TNF-α, and IL-6 [132]. The effect of FCN-A/2 on macrophage phenotype is mainly due to its stimulation of the MAPK/NF-κB signaling pathway, which further exacerbates IBD [132]. These pieces of evidence show that FCN-A/2 may be a potential target for the treatment of IBD.
Ficolin-1 and ficolin-3 polymorphisms and susceptibility to rheumatoid arthritis
Published in Autoimmunity, 2020
Cristhine Pieczarka, Fabiana Antunes Andrade, Sandra Jeremias Catarino, Kárita Cláudia Freitas Lidani, Lorena Bavia, Regina Tizzot, Thelma Skare, Iara Jose de Messias-Reason
In silico analyses performed here indicated that the c.-542G>A FCN1polymorphism associated with RA is located in a position enriched for typical histone modifications known to characterize chromatin signatures associated with regulatory sequences of active genes [35]. Distinct regulatory proteins were also observed binding to this region, as seen by chromatin immunoprecipitation assay in different cell lines (http://genome.ucsc.edu/). Additional evidence demonstrates at least 11 transcription factors recognizing the c.-542G>A FCN1 polymorphism region [36,37], indicating its possible involvement in the regulation of FCN1 gene expression. Interestingly, according to the GTEx database, the c.-542GG genotype is associated with lower FCN1 gene expression in some tissues, such as whole blood and adipose subcutaneous tissue (www.gtexportal.org). Lower ficolin-1 levels were also observed in the serum of c.-542GG blood donors [36,38], indicating a possible functional role for this polymorphism. Taken together, these findings may suggest a potential impact of c.-542GG genotype on FCN1 expression resulting in a lower serum concentration of ficolin-1 in RA patients. Nevertheless, the impact of the c.-542GG genotype in FCN1 gene expression and protein levels should be interpreted carefully since this was based on in silico analysis, genotype-tissue expression databases, and previous studies [36,38]. Future studies with a larger sample size are required in order to confirm the role of FCN1 polymorphisms in RA.
A new case of congenital ficolin-3 deficiency with primary immunodeficiency
Published in Expert Review of Clinical Immunology, 2020
Fateme Babaha, Hassan Abolhassani, Zahra Hamidi Esfahani, Reza Yazdani, Asghar Aghamohammadi
Ficolins are pattern recognition molecules (PRM) with a pivotal role in the activation of the lectin complement pathway. They recognize pathogen-associated molecular patterns (PAMPS) or damage-associated molecular patterns (DAMPs) on the surface of pathogens. The family of human ficolins comprises three oligomeric structured lectins: Ficolin-1 (M -ficolin), Ficolin-2 (L -ficolin) and Ficolin-3 (H -ficolin, Hakata antigen), which are encoded by FCN1, FCN2 and FCN3 genes, respectively [1,2]. Ficolins have important roles in the innate defense against bacterial and viral infection which their abnormal expression or dysfunction results in a pathogenic state of these organisms [3].