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1.
J Med Virol ; 94(1): 54-62, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34427929

RESUMO

Coronavirus disease 2019 (COVID-19) is still propagating a year after the start of the pandemic. Besides the complications patients face during the COVID-19 disease period, there is an accumulating body of evidence concerning the late-onset complications of COVID-19, of which autoimmune manifestations have attracted remarkable attention from the first months of the pandemic. Autoimmune hemolytic anemia, immune thrombocytopenic purpura, autoimmune thyroid diseases, Kawasaki disease, Guillain-Barre syndrome, and the detection of autoantibodies are the cues to the discovery of the potential of COVID-19 in inducing autoimmunity. Clarification of the pathophysiology of COVID-19 injuries to the host, whether it is direct viral injury or autoimmunity, could help to develop appropriate treatment.


Assuntos
Doenças Autoimunes/epidemiologia , Doenças Autoimunes/imunologia , Autoimunidade/imunologia , COVID-19/patologia , SARS-CoV-2/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Doenças Autoimunes/virologia , COVID-19/imunologia , Humanos
3.
Front Immunol ; 12: 708848, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659200

RESUMO

Impressive efforts have been made by researchers worldwide in the development of target vaccines against the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and in improving the management of immunomodulating agents. Currently, different vaccine formulations, such as viral vector, mRNA, and protein-based, almost all directed toward the spike protein that includes the domain for receptor binding, have been approved. Although data are not conclusive, patients affected by autoimmune rheumatic diseases (ARDs) seem to have a slightly higher disease prevalence, risk of hospitalization, and death from coronavirus disease-2019 (COVID-19) than the general population. Therefore, ARD patients, under immunosuppressive agents, have been included among the priority target groups for vaccine administration. However, specific cautions are needed to optimize vaccine safety and effectiveness in these patients, such as modification in some of the ongoing immunosuppressive therapies and the preferential use of mRNA other than vector-based vaccines. Immunomodulating agents can be a therapeutic opportunity for the management of COVID-19 patients; however, their clinical impact depends on how they are handled. To place in therapy immunomodulating agents in the correct window of opportunity throughout the identification of surrogate markers of disease progression and host immune response is mandatory to optimize patient's outcome.


Assuntos
Autoimunidade/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Hospedeiro Imunocomprometido/imunologia , Doenças Reumáticas/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , SARS-CoV-2/imunologia , Vacinação
4.
Front Immunol ; 12: 733418, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603311

RESUMO

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and abnormal fatigability due to the antibodies against postsynaptic receptors. Despite the individual discrepancy, patients with MG share common muscle weakness, autoimmune dysfunction, and immunosuppressive treatment, which predispose them to infections that can trigger or exacerbate MG. Vaccination, as a mainstay of prophylaxis, is a major management strategy. However, the past years have seen growth in vaccine hesitancy, owing to safety and efficacy concerns. Ironically, vaccines, serving as an essential and effective means of defense, may induce similar immune cross-reactivity to what they are meant to prevent. Herein, we outline the progress in vaccination, review the current status, and postulate the clinical association among MG, vaccination, and immunosuppression. We also address safety and efficacy concerns of vaccination in MG, in relation to COVID-19. Since only a handful of studies have reported vaccination in individuals with MG, we further review the current clinical studies and guidelines in rheumatic diseases. Overall, our reviews offer a reference to guide future vaccine clinical decision-making and improve the management of MG patients.


Assuntos
Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Miastenia Gravis/imunologia , Miastenia Gravis/patologia , SARS-CoV-2/imunologia , Autoimunidade/imunologia , Humanos , Tolerância Imunológica/imunologia , Vacinas contra Influenza/imunologia , Risco , Vacinação/efeitos adversos
6.
Nat Commun ; 12(1): 5565, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552089

RESUMO

Complex autoimmune diseases are sexually dimorphic. An interplay between predisposing genetics and sex-related factors probably controls the sex discrepancy in the immune response, but the underlying mechanisms are unclear. Here we positionally identify a polymorphic estrogen receptor binding site that regulates Cd2 expression, leading to female-specific differences in T cell-dependent mouse models of autoimmunity. Female mice with reduced Cd2 expression have impaired autoreactive T cell responses. T cells lacking Cd2 costimulation upregulate inhibitory Lag-3. These findings help explain sexual dimorphism in human autoimmunity, as we find that CD2 polymorphisms are associated with rheumatoid arthritis and 17-ß-estradiol-regulation of CD2 is conserved in human T cells. Hormonal regulation of CD2 might have implications for CD2-targeted therapy, as anti-Cd2 treatment more potently affects T cells in female mice. These results demonstrate the relevance of sex-genotype interactions, providing strong evidence for CD2 as a sex-sensitive predisposing factor in autoimmunity.


Assuntos
Doenças Autoimunes/genética , Antígenos CD2/genética , Predisposição Genética para Doença/genética , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Autoimunidade/genética , Autoimunidade/imunologia , Sítios de Ligação/genética , Antígenos CD2/imunologia , Antígenos CD2/metabolismo , Modelos Animais de Doenças , Estradiol/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Ativação Linfocitária , Masculino , Camundongos , Polimorfismo Genético , Caracteres Sexuais , Linfócitos T/imunologia
7.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445143

RESUMO

Dendritic cells (DCs) dictate the outcomes of tissue-specific immune responses. In the context of autoimmune diseases, DCs instruct T cells to respond to antigens (Ags), including self-Ags, leading to organ damage, or to becoming regulatory T cells (Tregs) promoting and perpetuating immune tolerance. DCs can acquire tolerogenic properties in vitro and in vivo in response to several stimuli, a feature that opens the possibility to generate or to target DCs to restore tolerance in autoimmune settings. We present an overview of the different subsets of human DCs and of the regulatory mechanisms associated with tolerogenic (tol)DC functions. We review the role of DCs in the induction of tissue-specific autoimmunity and the current approaches exploiting tolDC-based therapies or targeting DCs in vivo for the treatment of autoimmune diseases. Finally, we discuss limitations and propose future investigations for improving the knowledge on tolDCs for future clinical assessment to revert and prevent autoimmunity. The continuous expansion of tolDC research areas will lead to improving the understanding of the role that DCs play in the development and treatment of autoimmunity.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Células Dendríticas/imunologia , Tolerância Imunológica/imunologia , Animais , Humanos , Linfócitos T Reguladores/imunologia
8.
Nat Immunol ; 22(9): 1163-1174, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34426690

RESUMO

The immunosuppressive function of regulatory T (Treg) cells is dependent on continuous expression of the transcription factor Foxp3. Foxp3 loss of function or induced ablation of Treg cells results in a fatal autoimmune disease featuring all known types of inflammatory responses with every manifestation stemming from Treg cell paucity, highlighting a vital function of Treg cells in preventing fatal autoimmune inflammation. However, a major question remains whether Treg cells can persist and effectively exert their function in a disease state, where a broad spectrum of inflammatory mediators can either inactivate Treg cells or render innate and adaptive pro-inflammatory effector cells insensitive to suppression. By reinstating Foxp3 protein expression and suppressor function in cells expressing a reversible Foxp3 null allele in severely diseased mice, we found that the resulting single pool of rescued Treg cells normalized immune activation, quelled severe tissue inflammation, reversed fatal autoimmune disease and provided long-term protection against them. Thus, Treg cells are functional in settings of established broad-spectrum systemic inflammation and are capable of affording sustained reset of immune homeostasis.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Fatores de Transcrição Forkhead/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/genética , Diferenciação Celular/imunologia , Feminino , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica/genética , Homeostase/imunologia , Mediadores da Inflamação/metabolismo , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Resposta Inflamatória Sistêmica/patologia
9.
Elife ; 102021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34402793

RESUMO

Follicular T helper cells (Tfh) are a specialized subset of CD4 effector T cells that are crucial for germinal center (GC) reactions and for selecting B cells to undergo affinity maturation. Despite this central role for humoral immunity, only few data exist about their clonal distribution when multiple lymphoid organs are exposed to the same antigen (Ag) as it is the case in autoimmunity. Here, we used an autoantibody-mediated disease model of the skin and injected one auto-Ag into the two footpads of the same mouse and analyzed the T cell receptor (TCR)ß sequences of Tfh located in GCs of both contralateral draining lymph nodes. We found that over 90% of the dominant GC-Tfh clonotypes were shared in both lymph nodes but only transiently. The initially dominant Tfh clonotypes especially declined after establishment of chronic disease while GC reaction and autoimmune disease continued. Our data demonstrates a dynamic behavior of Tfh clonotypes under autoimmune conditions and emphasizes the importance of the time point for distinguishing auto-Ag-specific Tfh clonotypes from potential bystander activated ones.


Assuntos
Autoanticorpos/imunologia , Autoimunidade/imunologia , Centro Germinativo/imunologia , Linfonodos/imunologia , Células T Auxiliares Foliculares/imunologia , Animais , Antígenos/administração & dosagem , Antígenos/imunologia , Linfócitos B/imunologia , Feminino , Imunidade Humoral , Imunização , Linfonodos/citologia , Camundongos , Camundongos Endogâmicos C57BL
10.
Nat Immunol ; 22(9): 1107-1117, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34385713

RESUMO

The linkage between neutrophil death and the development of autoimmunity has not been thoroughly explored. Here, we show that neutrophils from either lupus-prone mice or patients with systemic lupus erythematosus (SLE) undergo ferroptosis. Mechanistically, autoantibodies and interferon-α present in the serum induce neutrophil ferroptosis through enhanced binding of the transcriptional repressor CREMα to the glutathione peroxidase 4 (Gpx4, the key ferroptosis regulator) promoter, which leads to suppressed expression of Gpx4 and subsequent elevation of lipid-reactive oxygen species. Moreover, the findings that mice with neutrophil-specific Gpx4 haploinsufficiency recapitulate key clinical features of human SLE, including autoantibodies, neutropenia, skin lesions and proteinuria, and that the treatment with a specific ferroptosis inhibitor significantly ameliorates disease severity in lupus-prone mice reveal the role of neutrophil ferroptosis in lupus pathogenesis. Together, our data demonstrate that neutrophil ferroptosis is an important driver of neutropenia in SLE and heavily contributes to disease manifestations.


Assuntos
Ferroptose/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Neutropenia/patologia , Neutrófilos/imunologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Autoanticorpos/imunologia , Autoimunidade/imunologia , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Humanos , Interferon-alfa/imunologia , Camundongos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Regiões Promotoras Genéticas/genética , Espécies Reativas de Oxigênio/metabolismo
11.
Cells ; 10(8)2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34440825

RESUMO

Autoimmune diseases are among the most common chronic illness caused by a dysregulated immune response against self-antigens. Close to 5% of the general population in Western countries develops some form of autoimmunity, yet its underlying causes, although intensively studied, are still not fully known, and no curative therapies exist. It is well established that autoimmune diseases have common mechanisms and are caused by both genetic and non-genetic risk factors. One novel risk factor that can contribute to autoimmunity is somatic mutations, in a role parallel to their role in cancer. Somatic mutations are stochastic, de novo, non-inherited mutations. In this hypothesis, the persistent proliferation of self-reactive lymphocytes (that is usually hindered by a series of checkpoints) is permitted, due to somatic mutations in these expanding cells, allowing them to bypass multiple regulatory checkpoints, causing autoimmunity. This novel concept of the contribution of these mutations in non-malignant diseases has recently started to be explored. It proposes a novel paradigm for autoimmunity etiology and could be the missing piece of the autoimmunity puzzle.


Assuntos
Autoimunidade/genética , Mutação , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Autoimunidade/imunologia , Proliferação de Células/genética , Humanos , Linfócitos/imunologia , Linfócitos/patologia
12.
Ann Rheum Dis ; 80(10): 1268-1277, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34380700

RESUMO

Increasingly earlier identification of individuals at high risk of rheumatoid arthritis (RA) (eg, with autoantibodies and mild symptoms) improves the feasibility of preventing or curing disease. The use of antigen-specific immunotherapies to reinstate immunological self-tolerance represent a highly attractive strategy due to their potential to induce disease resolution, in contrast to existing approaches that require long-term treatment of underlying symptoms.Preclinical animal models have been used to understand disease mechanisms and to evaluate novel immunotherapeutic approaches. However, models are required to understand critical processes supporting disease development such as the breach of self-tolerance that triggers autoimmunity and the progression from asymptomatic autoimmunity to joint pain and bone loss. These models would also be useful in evaluating the response to treatment in the pre-RA period.This review proposes that focusing on immune processes contributing to initial disease induction rather than end-stage pathological consequences is essential to allow development and evaluation of novel immunotherapies for early intervention. We will describe and critique existing models in arthritis and the broader field of autoimmunity that may fulfil these criteria. We will also identify key gaps in our ability to study these processes in animal models, to highlight where further research should be targeted.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Autoimunidade/imunologia , Imunoterapia , Tolerância a Antígenos Próprios/imunologia , Animais , Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Experimental/prevenção & controle , Artrite Experimental/terapia , Artrite Reumatoide/prevenção & controle , Artrite Reumatoide/terapia , Doenças Assintomáticas , Dessensibilização Imunológica , Modelos Animais de Doenças , Progressão da Doença , Tolerância Imunológica/imunologia , Camundongos , Ratos , Fator Reumatoide/imunologia
13.
Sci Rep ; 11(1): 15372, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321558

RESUMO

Pathogenesis of endometriosis is still unclear and a role of both innate and adaptive immune system has been postulated. Some recent findings have revealed an increased risk to have concomitant autoimmune disease in women with endometriosis, but no study so far has investigated whether this association could affect endometriosis severity and stage. We retrospectively reviewed medical patients' notes of women with a confirmed diagnosis of endometriosis who referred to our endometriosis outpatient clinic between January 2015 and December 2019. Cases (endometriosis and an autoimmune disease) were matched in a 1:3 ratio by age and study period with controls (endometriosis without history of autoimmunity). At univariate logistic analysis, concomitant autoimmunity (OR 2.63, 95% CI 1.64-4.21, p < 0.001) and the number of laparoscopic procedures performed (OR 2.81, 95% CI 1.45-5.43, p = 0.002) emerged as factors significantly associated with the likelihood of stage IV endometriosis. In the multivariate logistic regression model, concomitant autoimmunity remained a significant predictor of stage IV endometriosis (OR 2.54, 95% CI 1.57-4.10, p = 0.004), whereas the association between the number of laparoscopic procedures performed and stage IV endometriosis was found to be of borderline-significance (OR 2.70, 95% 1.37-5.30, p = 0.050). Our findings suggest that endometriosis is more severe in patients who are also affected by autoimmune disturbances after controlling for relevant confounders.


Assuntos
Autoimunidade/imunologia , Endometriose/diagnóstico , Endometriose/imunologia , Imunidade Adaptativa/imunologia , Adulto , Endometriose/patologia , Feminino , Humanos , Imunidade Inata/imunologia , Laparoscopia , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença
15.
J Immunol ; 207(2): 449-458, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34215657

RESUMO

Differentiation of Ag-specific B cells into class-switched, high-affinity, Ab-secreting cells provides protection against invading pathogens but is undesired when Abs target self-tissues in autoimmunity, beneficial non-self-blood transfusion products, or therapeutic proteins. Essential T cell factors have been uncovered that regulate T cell-dependent B cell differentiation. We performed a screen using a secreted protein library to identify novel factors that promote this process and may be used to combat undesired Ab formation. We tested the differentiating capacity of 756 secreted proteins on human naive or memory B cell differentiation in a setting with suboptimal T cell help in vitro (suboptimal CD40L and IL-21). High-throughput flow cytometry screening and validation revealed that type I IFNs and soluble FAS ligand (sFASL) induce plasmablast differentiation in memory B cells. Furthermore, sFASL induces robust secretion of IgG1 and IgG4 Abs, indicative of functional plasma cell differentiation. Our data suggest a mechanistic connection between elevated sFASL levels and the induction of autoreactive Abs, providing a potential therapeutic target in autoimmunity. Indeed, the modulators identified in this secretome screen are associated with systemic lupus erythematosus and may also be relevant in other autoimmune diseases and allergy.


Assuntos
Células Produtoras de Anticorpos/imunologia , Diferenciação Celular/imunologia , Proteína Ligante Fas/imunologia , Memória Imunológica/imunologia , Interleucinas/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Animais , Autoimunidade/imunologia , Linfócitos B/imunologia , Ligante de CD40/imunologia , Linhagem Celular , Células HEK293 , Humanos , Ativação Linfocitária/imunologia , Camundongos , Células NIH 3T3 , Plasmócitos/imunologia , Linfócitos T/imunologia
17.
Front Immunol ; 12: 650856, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211460

RESUMO

Accumulating evidence suggests that cholesterol accumulation in leukocytes is causally associated with the development of autoimmune diseases. However, the mechanism by which fatty acid composition influences autoimmune responses remains unclear. To determine whether the fatty acid composition of diet modulates leukocyte function and the development of systemic lupus erythematosus, we examined the effect of eicosapentaenoic acid (EPA) on the pathology of lupus in drug-induced and spontaneous mouse models. We found that dietary EPA supplementation ameliorated representative lupus manifestations, including autoantibody production and immunocomplex deposition in the kidneys. A combination of lipidomic and membrane dynamics analyses revealed that EPA remodels the lipid composition and fluidity of B cell membranes, thereby preventing B cell differentiation into autoantibody-producing plasma cells. These results highlight a previously unrecognized mechanism by which fatty acid composition affects B cell differentiation into autoantibody-producing plasma cells during autoimmunity, and imply that EPA supplementation may be beneficial for therapy of lupus.


Assuntos
Autoimunidade/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Suplementos Nutricionais , Ácido Eicosapentaenoico/farmacologia , Lúpus Eritematoso Sistêmico/prevenção & controle , Plasmócitos/efeitos dos fármacos , Animais , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Autoimunidade/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Células Cultivadas , Modelos Animais de Doenças , Ácido Eicosapentaenoico/administração & dosagem , Feminino , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Lúpus Eritematoso Sistêmico/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmócitos/imunologia , Plasmócitos/metabolismo
18.
Nat Rev Rheumatol ; 17(8): 449-461, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34226730

RESUMO

Infectious agents can trigger autoimmune responses in a number of chronic inflammatory diseases. Lyme arthritis, which is caused by the tick-transmitted spirochaete Borrelia burgdorferi, is effectively treated in most patients with antibiotic therapy; however, in a subset of patients, arthritis can persist and worsen after the spirochaete has been killed (known as post-infectious Lyme arthritis). This Review details the current understanding of the pathogenetic events in Lyme arthritis, from initial infection in the skin, through infection of the joints, to post-infectious chronic inflammatory arthritis. The central feature of post-infectious Lyme arthritis is an excessive, dysregulated pro-inflammatory immune response during the infection phase that persists into the post-infectious period. This response is characterized by high amounts of IFNγ and inadequate amounts of the anti-inflammatory cytokine IL-10. The consequences of this dysregulated pro-inflammatory response in the synovium include impaired tissue repair, vascular damage, autoimmune and cytotoxic processes, and fibroblast proliferation and fibrosis. These synovial characteristics are similar to those in other chronic inflammatory arthritides, including rheumatoid arthritis. Thus, post-infectious Lyme arthritis provides a model for other chronic autoimmune or autoinflammatory arthritides in which complex immune responses can be triggered and shaped by an infectious agent in concert with host genetic factors.


Assuntos
Doenças Autoimunes/imunologia , Borrelia burgdorferi/imunologia , Inflamação/imunologia , Doença de Lyme/imunologia , Doenças Autoimunes/microbiologia , Doenças Autoimunes/patologia , Autoimunidade/imunologia , Humanos , Inflamação/microbiologia , Inflamação/patologia , Doença de Lyme/microbiologia , Doença de Lyme/patologia
19.
Mol Immunol ; 137: 105-113, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34242919

RESUMO

Underlying mechanisms of multi-organ manifestations and exacerbated inflammation in COVID-19 are yet to be delineated. The hypothesis of SARS-CoV-2 triggering autoimmunity is gaining attention and, in the present study, we have identified 28 human proteins harbouring regions homologous to SARS-CoV-2 peptides that could possibly be acting as autoantigens in COVID-19 patients displaying autoimmune conditions. Interestingly, these conserved regions are amongst the experimentally validated B cell epitopes of SARS-CoV-2 proteins. The reported human proteins have demonstrated presence of autoantibodies against them in typical autoimmune conditions which may explain the frequent occurrence of autoimmune conditions following SARS-CoV-2 infection. Moreover, the proposed autoantigens' widespread tissue distribution is suggestive of their involvement in multi-organ manifestations via molecular mimicry. We opine that our report may aid in directing subsequent necessary antigen-specific studies, results of which would be of long-term relevance in management of extrapulmonary symptoms of COVID-19.


Assuntos
Autoantígenos/imunologia , Doenças Autoimunes/complicações , COVID-19/etiologia , Epitopos de Linfócito B/imunologia , SARS-CoV-2/imunologia , Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/virologia , Autoimunidade/imunologia , COVID-19/imunologia , COVID-19/patologia , Humanos , Mimetismo Molecular/imunologia
20.
Front Immunol ; 12: 683091, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220832

RESUMO

In human type 1 diabetes and animal models of the disease, a diverse assortment of immune cells infiltrates the pancreatic islets. CD8+ T cells are well represented within infiltrates and HLA multimer staining of pancreas sections provides clear evidence that islet epitope reactive T cells are present within autoimmune lesions. These bona fide effectors have been a key research focus because these cells represent an intellectually attractive culprit for ß cell destruction. However, T cell receptors are highly diverse in human insulitis. This suggests correspondingly broad antigen specificity, which includes a majority of T cells for which there is no evidence of islet-specific reactivity. The presence of "non-cognate" T cells in insulitis raises suspicion that their role could be beyond that of an innocent bystander. In this perspective, we consider the potential pathogenic contribution of non-islet-reactive T cells. Our intellectual framework will be that of a criminal investigation. Having arraigned islet-specific CD8+ T cells for the murder of pancreatic ß cells, we then turn our attention to the non-target immune cells present in human insulitis and consider the possible regulatory, benign, or effector roles that they may play in disease. Considering available evidence, we overview the case that can be made that non-islet-reactive infiltrating T cells should be suspected as co-conspirators or accessories to the crime and suggest some possible routes forward for reaching a better understanding of their role in disease.


Assuntos
Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/etiologia , Suscetibilidade a Doenças , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Autoimunidade/genética , Biomarcadores , Comunicação Celular/genética , Comunicação Celular/imunologia , Microambiente Celular/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Modelos Animais de Doenças , Humanos , Ilhotas Pancreáticas/patologia , Subpopulações de Linfócitos T/patologia
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