Immunogenetic Aspects Research Articles

Immunogenicity Parameters of Cancer Patients Receiving the mRNA Vaccine BNT162b2 While Obtaining Radiotherapy: A Longitudinal Cohort Evaluation.

Cancer patients are highly prone to infectious diseases. While undergoing antineoplastic treatment, the risk of severe symptoms upon infection increases, necessitating efficient protective measures, such as vaccination. For patients receiving radiotherapy, there is no specific information about humoral immunity. During the COVID-19 pandemic, serial antibody measurements were therefore offered to cancer patients, following SARS-CoV-2 vaccination while obtaining radiotherapy. Out of 74 enrolled patients, 46 met the inclusion criteria. Two cohorts were allocated, depending on an association with chemotherapy or pure radiotherapy. An additional healthy control cohort of 16 healthcare workers was enrolled. All participants followed a two-fold BNT162b2 vaccine schedule. SARS-CoV-2 binding antibodies were measured serially in a 7-day cycle for 35 days and over the long-term, using the Elecsys® Anti-SARS-CoV-2 immunoassay. Cancer patients under pure radiotherapy have a comparable humoral vaccination response and long-term persistency of antibodies to healthy controls. Patients receiving additional chemotherapy show a significantly delayed immune response and decreased antibody titers. The vaccine was well tolerated in all cohorts. Pure radiotherapy in cancer patients does not interfere with the vaccine-induced humoral immune response or other immunogenetic aspects, whereas previous or simultaneous chemotherapy does. Findings are of particular relevance for future epidemic or pandemic scenarios.

Immunogenetic Aspects of Sarcopenic Obesity.

Sarcopenic obesity (SO) is a combination of obesity and sarcopenia, with diagnostic criteria defined as impaired skeletal muscle function and altered body composition (e.g., increased fat mass and reduced muscle mass). The mechanism of SO is not yet perfectly understood; however, the pathogenesis includes aging and its complications, chronic inflammation, insulin resistance (IR), and hormonal changes. Genetic background is apparent in the pathogenesis of isolated obesity, which is most often polygenic and is characterized by the additive effect of various genetic factors. The genetic etiology has not been strictly established in SO. Still, many data confirm the existence of pathogenic gene variants, e.g., Fat Mass and Obesity Associated Gene (FTO), beta-2-adrenergic receptor (ADRB2) gene, melanocortin-4 receptor (MC4R) and others with obesity. The literature on the role of these genes is scarce, and their role has not yet been thoroughly established. On the other hand, the involvement of systemic inflammation due to increased adipose tissue in SO plays a significant role in its pathophysiology through the synthesis of various cytokines such as monocyte chemoattractant protein-1 (MCP-1), IL-1Ra, IL-15, adiponectin or CRP. The lack of anti-inflammatory cytokine (e.g., IL-15) can increase SO risk, but further studies are needed to evaluate the exact mechanisms of implications of various cytokines in SO individuals. This manuscript analyses various immunogenetic and non-genetic factors and summarizes the recent findings on immunogenetics potentially impacting SO development.

Иммуногенетические аспекты развития остеоартрита (обзор литературы)

Inflammation plays critical role in the onset and progression of osteoarthritis (OA), a joint disease affecting more than 10 % of the world's population. Exporing immunological mechanisms of osteoarthritis is essential. The present paper is a literature review of immunogenetic aspects of the pathogenesis of the disease. The study is aimed at analysis and summary of information concerning the immunogenetics and molecular mechanisms of osteoarthritis. Material and methods The original literature search was conducted on key resources including Scientific Electronic Library (www. elibrary.ru) and the National Library of Medicine (www.pubmed.org) with subsequent selection of articles, analysis and synthesis of information. Results and discussion Mutations in proinflammatory cytokine and receptor genes, metalloprotease genes, HLA genes and in the anti-inflammatory cytokine (IL-4) gene, polymorphisms in phospholipase and IL-2 genes are more common for OA patients than for healthy subjects. Epigenetic regulation in OA include a decreased methylation of the promoters of proinflammatory cytokine and metalloprotease genes and a decreased methylation of NF‑κB‑sensitive iNOS enhancer sites. OA patients show an increased activity of histone acetylases in the IL-6 promoter area. In contrast, the expression of anti-inflammatory cytokines is decreased due to the reduced activity of the SIRT1 deacetylase.

The Immunogenetic Aspects of Photodynamic Therapy.

Photodynamic therapy (PDT) has become the first-line treatment of actinic keratosis, superficial basal cell carcinoma, and squamous cell carcinoma in situ (Bowen's disease) in dermatology. The off-label use of PDT has also escalated in recent years owing to its applications in the treatment of various non-neoplastic skin diseases such as acne vulgaris, vascular lesions, rejuvenation, and chronic wounds. Daylight PDT that uses natural sunlight to activate a photosensitizer with advantages such as low cost and reduced pain is widely used in Europe. This chapter reviews the applications and immunogenetic aspects of PDT. However, the studies of immunity and genetic changes in human tissue after PDT are limited.

Immunogenetic aspects of idiopathic recurrent miscarriage in the Kazakh population.

There are numerous scientific studies of recurrent miscarriage (RM) with possible causes, such as fetal chromosomal abnormalities, infectious agents, adverse environmental factors, bad habits, anatomical defects, thrombophilic disorders, etc. However, RM causes in 50% of cases remain unknown. These RM cases do not have any explainable etiology, and they require in-depth etiopathogenesis study, thus they are considered idiopathic RM. The purpose of this research is to study polymorphisms relationship of the immune response genes CX3CR1 (rs3732379, Val249Ile), CTLA4 (rs3087243, CT60 G/A), and HLA DQA1, DQB1, DRB1 (major histocompatibility complex, class II) with the idiopathic form of recurrent miscarriage (iRM) development in Kazakh population. Independent replicative TagMan genotyping for 302 patients with iRM and 300 women with normal reproduction was performed. It has been shown that carriage of unfavorable genotypes (Val/Ile, Val/Val) by the Val249Ile polymorphism of the CX3CR1 gene increases the risk of developing iRM by 1.43 times. Search for associations of genes allelic variants of HLA class 2 complex with iRM revealed *501 allele in DQA1 locus, *0301 in DQB1 locus, *10, *12, *15, *16 alleles in DRB1 locus, which increases the risk of developing iRM in Kazakh population with OR from 1.34 to 4.5. As a result of the study, obtained highly significant associations of immune response genes with the development of iRM in the Kazakh population indicate the possible involvement of the immune system interaction of mother cells with syncytiotrophoblast, which is realized by vascularization defects, defective embryo implantation, and leads to early pregnancies’ termination.

Role of Immunogenetics in the Outcome of HCMV Infection: Implications for Ageing.

The outcome of host-virus interactions is determined by a number of factors, some related to the virus, others to the host, such as environmental factors and genetic factors. Therefore, different individuals vary in their relative susceptibility to infections. Human cytomegalovirus (HCMV) is an important pathogen from a clinical point of view, as it causes significant morbidity and mortality in immunosuppressed or immunosenescent individuals, such as the transplanted patients and the elderly, respectively. It is, therefore, important to understand the mechanisms of virus infection control. In this review, we discuss recent advances in the immunobiology of HCMV-host interactions, with particular emphasis on the immunogenetic aspects (human leukocyte antigens, HLA; killer cell immunoglobulin-like receptors, KIRs; immunoglobulin genetic markers, GM allotypes) to elucidate the mechanisms underlying the complex host-virus interaction that determine various outcomes of HCMV infection. The results, which show the role of humoral and cellular immunity in the control of infection by HCMV, would be valuable in directing efforts to reduce HCMV spurred health complications in the transplanted patients and in the elderly, including immunosenescence. In addition, concerning GM allotypes, it is intriguing that, in a Southern Italian population, alleles associated with the risk of developing HCMV symptomatic infection are negatively associated with longevity.

Clinical and Immunogenetic Aspects of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease triggered by a complex interaction of immunologic, environmental, and genetic factors. Like other diseases of autoimmune origin, SLE manifestations follow relapsing and remitting courses. Several lines of evidence have demonstrated the association of adaptive and innate immune responses with regulation in SLE pathogenesis. The immunological diagnosis primarily relies on detection of serum autoantibodies in SLE patients. A concordance rate of < 25% between monozygotic twins indicates potential involvement of environmental factors in SLE development. In addition, SLE is categorized by a wide range of clinical manifestations, partly related to the disease itself but also associated with comorbidities and adverse drug reactions. Because the common therapeutic strategies are connected with certain adverse events, immunosuppressive medications and biological agents are used on the basis of prevailing disease manifestations. Genome-wide association studies have identified 50 loci that influence SLE. However, the actual genetic polymorphism that imparts SLE risk is not fully known. Further understanding can help to expand quality of life in SLE individuals.

Next-Generation Sequencing Based HLA Typing: Deciphering Immunogenetic Aspects of Sarcoidosis.

Unraveling of the HLA-related immunogenetic basis of several immune disorders is complex due to the extensive HLA polymorphism and strong linkage-disequilibrium between HLA loci. A lack of in phase sequence information, a relative deficiency of high resolution genotyping including non-coding regions and ambiguous haplotype assignment make it difficult to compare findings across association studies and to attribute a causal role to specific HLA alleles/haplotypes in disease susceptibility and modification of disease phenotypes. Earlier, historical antibody and DNA-based methods of HLA typing, primarily of low resolution at antigen/alellic group levels, yielded “indicative” findings which were partially improved by high-resolution DNA-based typing. Only recently, next-generation sequencing (NGS) approaches based on deep-sequencing of the complete HLA genes combined with bioinformatics tools began to provide the access to complete information at an allelic level. Analyzing HLA with NGS approaches, therefore, promises to provide further insight in the etiopathogenesis of several immune disorders in which HLA associations have been implicated. These range from coeliac disease and rheumatological conditions to even more complex disorders, such as type-1 diabetes, systemic lupus erythematosus and sarcoidosis. A systemic disease of unknown etiology, sarcoidosis has previously been associated with numerous HLA variants and also other gene polymorphisms, often in linkage with the HLA region. To date, the biological significance of these associations has only partially been defined. Therefore, more precise assignments of HLA alleles/haplotypes using NGS approaches could help to elucidate the exact role of HLA variation in the multifaceted etiopathogenesis of sarcoidosis, including epigenetic mechanisms. NGS-based HLA analyses may be also relevant for defining variable clinical phenotypes and for predicting the disease course or the response to current/plausible novel therapies.

Autoimmune and immunogenetic profile of patients with optic neuritis in a population-based cohort

BackgroundOptic neuritis (ON) is an inflammatory optic neuropathy, where the genetic and autoimmune dependency remains poorly characterized. ObjectiveTo investigate autoimmune and immunogenetic aspects of ON. MethodIn a prospective population-based cohort 51 patients with ON were included. At follow up 20 patients had progressed to multiple sclerosis (MS-ON). All patients were screened for neuronal and systemic autoantibodies. HLA genotypes and allele and genotype frequencies of the PTPN22 C1858T and the PD-1.3 single-nucleotide polymorphisms (SNPs) were determined and compared to a cohort of Danish blood donors, acting as healthy controls. ResultsMedian follow-up was 366 days (301−430) for MS-ON patients and 375 (range 50–436) for isolated ON (ION). Autoantibodies against myelin oligodendrocyte glycoprotein (MOG-IgG), were positive in two patients, no patients had anti-aquaporin-4 antibodies. Coexisting neural autoantibodies were detected in two patients and in 12 patients other systemic autoantibodies were found. Four (8%) had other autoimmune disorders. A family history of autoimmunity was observed in 12 (24%) and of demyelinating disease in six patients (12%). In MS-ON patients the frequencies of HLA-DQB1*06:02 and HLA-DRB1*15:01 tended to be higher compared to controls (p = 0.08). Stratification of patients with presence of oligoclonal bands (OCB) showed an association to the HLA-DQB1*06:02-HLA-DRB1*15:01 haplotype in ION (HLA-DQB1*06:02 and HLA-DRB1*15:01 (p = 0.03)), and in MS-ON patients (HLA-DQB1*06:02 and HLA-DRB1*15:01 (p = 0.03)). No significant associations to PTPN22 1858C/T or PD-1.3 G/A were found in any group comparison. ConclusionsON patients had a general susceptibility to autoimmunity and two were MOG-IgG positive. HLA-DQB1*06:02 and HLA-DRB1*15:01 were associated with the presence of OCB in ON patients.

CHRONIC UTERINE INFLAMMATION: SOME PATHOGENETIC ASPECTS

Currently, molecular-genetic studies attract attention of many scientists; there are contradictory and ambiguous data on some genes and their role in chronic inflammations of pelviс organs. Some immunogenetic aspects of pathogenesis of chronic endometritis are presented in this review; the role of mutual effect of gene dysregulation and immune system is indicated, the data on possible link between functional endometrium status and pathological polymorphism of some genes are cited.

Psoriatic Inflammation Facilitates the Onset of Arthritis in a Mouse Model

Psoriatic arthritis (PsA) is a seronegative, inflammatory joint disease associated with psoriasis. In most patients with PsA, skin lesions precede arthritis; however, the causality of skin inflammation for the development of arthritis remains unclear. Gp130F759/F759 knock-in (F759) mice develop autoimmune arthritis after 1 year of age through persistent signal transducer and activator of transcription 3 (Stat3) activation due to impairment in SOCS3-dependent negative regulation. Here, we crossed F759 mice with K5.Stat3C transgenic mice, in which keratinocytes express constitutive active Stat3 (Stat3C), leading to generation of psoriasis-like skin change. F759 mice harboring the K5.Stat3C transgene not only had aggravated skin lesions but also spontaneously developed arthritis with high penetrance in adjacent paws as early as 3 weeks of age. The joint lesions included swelling of the peripheral paws and nail deformities contiguous with the skin lesions, closely resembling PsA. Histopathologic study revealed enthesitis and bone erosions, with mononuclear cell infiltrates. Quantitative reverse transcriptase-PCR (RT-PCR), immunohistochemical analyses, and flow cytometry showed upregulation of the IL-23/T helper type 17 (Th17) pathway in affected joints. Furthermore, enforced generation of psoriasis-like skin inflammation by topical treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) in F759 mice induced swelling of the underlying joints. This animal model renders psoriatic inflammation as the driver of arthritis and helps to further understand the pathogenesis of PsA.

Analysis of HLA class II alleles (DQ - DR) in patients with gastric diseases caused by Helicobacter pylori, in the city of Barranquilla, Colombia.

Analysis of HLA class II alleles (DQ - DR) in patients with gastric diseases caused by Helicobacter pylori, in the city of Barranquilla, Colombia.

ALLELIC POLYMORPHISM OF IFNγ GENE IN PATIENTS WITH PULMONARY TUBERCULOSIS

In present work, some immunogenetic aspects of pulmonary tuberculosis were studied, using modern techniques from molecular genetics and immunology. It is shown that carriage of Т allele and homozygous TT genotype in +874А/Т IFNγ gene polymorphism comprise a immunogenetic factor which correlated with a protective effect, regarding a susceptibility to pulmonary tuberculosis. Predisposition for tuberculosis infection is associated with A allele of this gene, as well as with АА and АТ genotypes of +874A/T IFNγ gene. Clinical evolution of pulmonary tuberculosis is accompanied by increase in IFNγ production.

Autoimmune polyendocrine syndrome type 1: case report and review of literature

Autoimmune polyendocrine syndrome type 1 (APECED) is a rare autosomal recessive disorder characterized by autoimmune multiorgan attack. The disease is caused by mutations in the autoimmune regulator gene (AIRE), resulting in defective AIRE protein, which is essential for selftolerance. Clinical manifestations are widely variable. Although the classic triad is composed by mucocutaneous candidiasis, hypoparathyroidism and adrenal failure, many other components may develop. Treatment is based on supplementation of the various deficiencies, and patients require regular follow-up throughout their lifespan. This article describes the case of a patient with the disease, and reviews literature data on the epidemiology, clinical course, immunogenetic aspects, diagnosis and treatment of the syndrome.

Actinic cheilitis and squamous cell carcinoma of the lip: clinical, histopathological and immunogenetic aspects

Actinic cheilitis is the main precancerous lesion of the lip. Squamous cell carcinoma of the lip is reported together with oral carcinomas in the Brazilian official statistics. Overall, they account for 40% of the head and neck carcinomas. In general, physicians and dentists know little about what causes oral tumor development and progression. Tumor suppressor genes and cell proliferation regulatory proteins play a role in the progression of actinic cheilitis to squamous cell carcinoma and in its biological behavior. Knowledge on prognostic and diagnostic markers has a positive impact on the follow-up of these patients.

Churg–Strauss syndrome

Churg-Strauss syndrome (CSS) has a clear clinical phenotype but its pathogenesis is not fully elucidated. Recent studies have focused on its immunogenetic aspects and cytokine and chemokine-mediated pathogenetic mechanisms, providing the rationale for the use of newer targeted therapies. This study will review recent findings on the pathogenesis of CSS and its therapeutic approaches. CSS is usually considered a Th2-mediated disease, but Th1 and Th17 responses might also play a role; the reported association between CSS and HLA-DRB4 further underlines the pathogenetic relevance of CD4 T cells which, thanks to their ability to secrete cytokines such as IL4, IL5, and IL13, promote allergic and eosinophilic reactions. Resident cells such as endothelial and epithelial cells might also amplify the immune response by producing eosinophil-attracting chemokines such as eotaxin-3 and CCL17. Conventional immunosuppressive therapies offer high chances of achieving sustained remission, but steroid exposure remains high. Targeting IL5 with mepolizumab seems promising in sparing steroids, but relapses often follow its withdrawal. B-cell depletion using rituximab has proved effective in refractory CSS cases. Current knowledge on CSS pathogenesis is evolving; the identification of key molecular mechanisms will pave the way for newer, more specific treatments.

Immunological Aspects of Human Reproduction

The scientific community of immunologists has been interested in immunological aspects of reproduction since the beginning of last century. Although many questions of reproductive immunology still remain unanswered, several important results have been obtained during recent years. Most importantly, the topic has achieved more wider impact than before. Presently, immunology of human reproduction involves not only the interaction between the maternal immune system and the fetus-placenta status, but also many diverse aspects of reproduction ranging from human gametogenesis to immuno(epi)genetic aspects of diseases of the reproductive system of females and males. Since fertility rates are falling in many countries implying wider usage of various assisted reproduction technologies to overcome reproductive failure, the topic of immunology of human reproduction is receiving increasing attention. Conversely, immunology journals are publishing more papers on every aspect of the immunology of reproduction. The completion of this special issue of Clinical and Developmental Immunology is a good example.

Therapeutic Dosing of Fingolimod (FTY720) Prevents Cell Infiltration, Rapidly Suppresses Ocular Inflammation, and Maintains the Blood-Ocular Barrier

Fingolimod (FTY720) is an FDA-approved therapeutic drug with efficacy demonstrated in experimental models of multiple sclerosis and in phase III human multiple sclerosis trials. Fingolimod prevents T-cell migration to inflammatory sites by decreasing expression of the sphingosine-1 phosphate receptor normally required for egress from secondary lymphoid tissue. As a preclinical model of human uveitis, experimental autoimmune uveoretinitis permits assessment of immunotherapeutic efficacy. Murine experimental autoimmune uveoretinitis is induced by activation of retinal antigen-specific CD4(+) T cells that infiltrate the eye. High-dose fingolimod treatment administered before disease onset reduces ocular infiltration within hours of administration and suppresses clinicopathologic expression of experimental autoimmune uveoretinitis. In the present investigation of the efficacy of fingolimod treatment for established disease, single-dose treatment was effective and immunosuppressive ability was maintained through a dose range, demonstrating significant and rapid reduction in CD4(+) cell infiltration at clinically relevant therapeutic doses of fingolimod. A repeated-treatment regimen using a dose similar to that in current multiple sclerosis patient protocols significantly reduced infiltration within 24 hours of administration; importantly, repeated doses did not compromise the vascular integrity of the blood-ocular barrier. On withdrawal of fingolimod, drug-induced remission was lost and recrudescence of clinical disease was observed. These results support a strong therapeutic potential for fingolimod as an acute rescue therapy for the treatment of ocular immune-mediated inflammation.

HLA, PTPN22 and PD-1 associations as markers of autoimmunity in neuromyelitis optica

Background: Neuromyelitis optica (NMO) is a disease with autoimmune characteristics. A genetic autoimmune dependency for NMO has not been clarified in detail. Objective: To investigate immunogenetic aspects of NMO. Methods: Forty-one patients with NMO and 42 patients with multiple sclerosis (MS) were diagnosed in a population-based Caucasian cohort. HLA DQA1, DQB1, and DRB1 alleles were determined. Polymorphisms in programmed death 1 (PD-1) PD-1.3 G/A and protein tyrosine phosphatase non-receptor 22 (PTPN22) 1858 C/T were genotyped. Results: In the NMO group 15% had other autoimmune disorders and 39% had family occurrence of autoimmunity, comparable to MS. A higher frequency of a family history (17%) of NMO and MS was found in the NMO group (p < 0.026). The frequency of HLA-DQB1*0402 allele was increased in NMO (p after Bonferroni correction, cp < 0.035) and the HLA-DRB1*15 and DQB1*06 alleles were increased in MS (cp < 0.0027, cp < 0.01), compared to controls. No associations of the PTPN22 1858 T were detected. The PD-1.3A allele was increased both in NMO (p < 0.0023) and in MS patients (p < 0.028) compared to controls. Conclusion: Patients with NMO had frequent co-existence of autoimmunity and family occurrence of NMO and MS. The PD-1.3A allele was associated with NMO. The data suggest genetic autoimmune dependency of NMO.

Clinical, immunological, and genetic aspects in leprosy

AbstractLeprosy is a chronic infection caused by Mycobacterium leprae. It affects the skin and peripheral nerves and can cause irreversible chronic disabilities. The worldwide registered number of cases in 2009 was 213,036. This review discusses clinical aspects of the disease, including leprosy reactions and neuronal damage, as well as immunological and immunogenetic aspects influencing disease susceptibility and outcome. The cardinal signs of leprosy are skin lesions with altered sensation, thickened peripheral nerves, and presence of alcohol acid‐resistant bacilli in skin biopsy or lymph. Confirmatory examinations include (1) bacteriological examination, which allows patients' classification into two operational groups, multibacillary (MB) and paucibacillary (PB); and (2) histopathological examination, which permits stratification in different clinical forms. These clinical forms differ not only by histopathology but also according to the host's immune response to M. leprae. These forms comprise the extremes of (1) tuberculoid leprosy (TT), with a specific Th1 response and control of M. leprae multiplication; (2) lepromatous leprosy (LL) without Th1 response and preserved Th2 response; and (3) the interpolar clinical forms, borderline tuberculoid (BT), borderline borderline (BB), borderline lepromatous (BL), and indeterminate form (IL). Appropriate treatment is based on smear examination or the number of lesions at diagnosis. In the evolution of leprosy, acute inflammation, known as reactions, may occur during or after treatment. These reactions are classified into two main types: the type I reaction or reversal reaction (RR), and the type II reaction or erythema nodosum leprosum (ENL). The role of innate immune response to control the infection is supported by immunological and genetic studies. Drug Dev Res 72:509–527, 2011. © 2011 Wiley‐Liss, Inc.