Autoantibodies as predictors of disease

Leslie, David; Lipsky, Peter E.; Notkins, Abner Louis

doi:10.1172/jci14452

Cited by 168 publications

(96 citation statements)

References 61 publications

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“…Nevertheless, studies on NOD mice devoid of B cells have shown that this lymphocyte population is necessary in the diabetic autoimmune process [4] and it is widely accepted that islet-related autoantibodies (AAbs) represent the earliest manifestations of diabetogenesis in both prediabetic patients and in NOD mice [5]. These autoreactive immunoglobulins, of the IgG isotype, recognise beta cell antigens and are believed to be bystander products of the disease resulting from an ongoing autoimmune process [5]. Thus, at the stage of cytotoxic beta cell destruction, B cells would be highly exposed to beta cell-related autoantigens (AAgs), leading to preferential activation of B cells with autoreactive potential.…”

Section: Introductionmentioning

confidence: 99%

Innate stimulation of B1a cells enhances the autoreactive IgM repertoire in the NOD mouse: implications for type 1 diabetes

Côrte‐Real

Duarte

Tavares³

et al. 2012

Diabetologia

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Aims/hypothesis We sought to determine whether the presence of natural autoreactive antibodies of B1a cell origin would play a role in the initiation of type 1 diabetes. Methods We compared IgM repertoires and B1a cell compartments in NOD and C57BL/6 mice. Serum IgM autoreactivity profiles were determined by ELISA and the secretory properties and activation status of B1a cells were characterised by enzyme-linked immunosorbent spot (ELI-SPOT) assay and flow cytometry. B1a cell response to innate activation was analysed by gene expression assays, ELISA and [ 3 H]thymidine incorporation. The effect of NOD IgM produced by B1a cells on NOD.severe combined immunodeficient (SCID) beta cells was examined in cocultures: IgM binding was measured by flow cytometry and real-time PCR was used to study oxidative stress responses.Results NOD mice displayed increased levels of serum antiinsulin IgM that were independent of the H2 locus, that were maintained up to prediabetic stages and that correlated with the NOD B1a cell secretion profile. NOD B1a cells had a naturally increased pattern of activation, expressed higher levels of toll-like-receptors (Tlrs) and responded to TLR stimulation in vitro with higher proliferation and increased capacity to secrete anti-type-1-diabetes-related IgM, but produced lower amounts of IL10. IgM of NOD B1a cell origin was able to bind to pancreatic beta cells in vitro and induce expression of inducible nitric oxide synthase (Nos2). Conclusions/interpretation NOD B1a cells had a lower innate activation threshold for secretion of autoreactive IgM capable of triggering oxidative stress responses on binding to pancreatic beta cells; this provides an early mechanism that contributes to diabetes in a mouse model of type 1 diabetes.

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Section: Introductionmentioning

confidence: 99%

Innate stimulation of B1a cells enhances the autoreactive IgM repertoire in the NOD mouse: implications for type 1 diabetes

Côrte‐Real

Duarte

Tavares³

et al. 2012

Diabetologia

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“…Однако обнаружение аутоантител различной специфич-ности в периферической крови может иметь зна-чительную прогностическую ценность и отра-жать тяжесть заболевания [12].…”

Section: Introductionunclassified

Foxp3+t-Regulatory Lymphocytes and Autoantibodies in Patients With Arterial Hypertension, Associated With Diabetes Mellitus Type 2 and Impaired Glucose Tolerance

Степанова¹,

Козонов²,

Tsitskarava³

et al. 2014

Med.Imm.Rus

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FoxP3+ Т-регуляТорные лимфоциТы и ауТоанТиТела при арТериальной гиперТензии, ассоциированной с сахарным диабеТом 2-го Типа и нарушением ТолеранТносТи к углеводам Кологривова И.В., Суслова Т.Е., Кошельская О.А., Винницкая И.В., Трубачева О.А., Желтоногова Н.М., Гусакова А.М. Федеральное государственное бюджетное учреждение «Научно-исследовательский институт кардиологии» Сибирского отделения Российской академии медицинских наук, г. Томск, РоссияРезюме. Показано, что для пациентов с артериальной гипертензией, ассоциированной с сахар-ным диабетом 2-го типа, характерно снижение содержания FoxP3 + Т-регуляторных клеток и повыше-ние уровня антител к ткани сердца и ядерным антигенам. При сочетании нарушения толерантности к углеводам и артериальной гипертензии низкому количеству Т-регуляторных лимфоцитов сопут-ствовало повышенное содержание ревматоидного фактора и антимитохондриальных антител. Арте-риальная гипертензия ассоциировалась с дислипидемией и сопровождалась увеличением концентра-ции ревматоидного фактора и антител к ядерным антигенам. Во всех группах пациентов выявлены тесные корреляционные связи между содержанием аутоантител, количеством FoxP3 + Т-регуляторных лимфоцитов и параметрами углеводного и липидного обмена. Полученные результаты свидетель-ствуют об ассоциации метаболических расстройств с нарушениями механизмов аутотолерантности в гуморальном звене иммунной системы, что проявляется уже на ранних этапах формирования са-харного диабета 2-го типа и может вносить вклад в развитие осложнений при данном заболевании. Оригинальные статьиOriginal articles Медицинская иммунология 2013, Т. 15, № 2, стр. 155-162 © 2013, СПб РО РААКИ Medical Immunology 2013, Vol. 15, 2, pp.155-162 © 2013 Research Institute of Cardiology, Russian Academy of Medical Sciences, Siberian Branch, Tomsk, Russian FederationAbstract. When studying patients with an association of arterial hypertension and type 2 diabetes mellitus, we have shown a lower number of FoxP3 + T-regulatory cells, as well as elevated levels of anti-myocardial antibodies and autoantibodies to nuclear antigens. In a group with combination of impaired glucose tolerance and arterial hypertension, a decrease in T-regulatory lymphocytes' numbers, along with increased rheumatoid factor and antimitochondrial autoantibodies concentrations were observed. Arterial hypertension was combined with dyslipidemia, being accompanied by higher levels of rheumatoid factor and antibodies to nuclear antigens. In all these clinical groups, we revealed close correlations between concentrations of autoantibodies, FoxP3 + Tregulatory lymphocyte scores, and parameters of carbohydrate and lipid metabolism. The results, obtained in present study, allow us to suggest that metabolic disturbances may be associated with altered immune tolerance mechanisms and activation of humoral immune response that are detectable since early stages of the disease and may contribute to development of complications occurring in diabetes mellitus type 2. (Med. Immunol., 2013, vol. 15, N 2, pp 155-162)

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“…Similarly, a high proportion of autoreactive B cells can be found in the periphery [12]. The immune repertoire therefore contains autoreactive lymphocytes that can cause destruction of the host tissues or reject tumours, when activated properly.…”

Section: Introductionmentioning

confidence: 99%

Does our Current Understanding of Immune Tolerance, Autoimmunity, and Immunosuppressive Mechanisms Facilitate the Design of Efficient Cancer Vaccines?

Sioud

2009

Scand J Immunol

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The therapeutic use of the immune system to attack cancer cells has been a longstanding vision among tumour immunologists. However, most human tumours are poorly immunogenic and are able to invade the host immune system. Although these obstacles are clearly critical to cancer vaccine development, the induction of a strong anti‐tumour immune response may rely on the activation of high affinity T cells through a molecular mimicry mechanism which involves cross‐reactive recognition of foreign antigens mimicking the structure of tumour proteins. Taking into account the disparity in HLA molecules needed to present shared antigens; in late 1990s Stauss et al. described the possibility of generating allorestricted high affinity cytotoxic T cells against synthetic self‐peptides bound to non‐self‐MHC molecules. In addition to the strategies indicated above, the inhibition of the immunosuppressive mechanisms associated with tumour invasion of the immune system using RNA interference also offers a new approach to vaccine design. This review highlights the problem of immune tolerance, the induction of autoreactive T cells, and describes strategies to enhance tumour immunity.

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Autoantibodies as predictors of disease

Cited by 168 publications

References 61 publications

Innate stimulation of B1a cells enhances the autoreactive IgM repertoire in the NOD mouse: implications for type 1 diabetes

Innate stimulation of B1a cells enhances the autoreactive IgM repertoire in the NOD mouse: implications for type 1 diabetes

Foxp3+t-Regulatory Lymphocytes and Autoantibodies in Patients With Arterial Hypertension, Associated With Diabetes Mellitus Type 2 and Impaired Glucose Tolerance

Does our Current Understanding of Immune Tolerance, Autoimmunity, and Immunosuppressive Mechanisms Facilitate the Design of Efficient Cancer Vaccines?

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