PMID- 33071971 OWN - NLM STAT- MEDLINE DCOM- 20210526 LR - 20210526 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 11 DP - 2020 TI - Enterovirus Neutralizing Antibodies, Monocyte Toll Like Receptors Expression and Interleukin Profiles Are Similar Between Non-affected and Affected Siblings From Long-Term Discordant Type 1 Diabetes Multiplex-Sib Families: The Importance of HLA Background. PG - 555685 LID - 10.3389/fendo.2020.555685 [doi] LID - 555685 AB - Enteroviruses are main candidates among environmental agents in the development of type 1 diabetes (T1D). However, the relationship between virus and the immune system response during T1D pathogenesis is heterogeneous. This is an interesting paradigm and the search for answers would help to highlight the role of viral infection in the etiology of T1D. The current data is a cross-sectional study of affected and non-affected siblings from T1D multiplex-sib families to analyze associations among T1D, genetic, islet autoantibodies and markers of innate immunity. We evaluated the prevalence of anti-virus antibodies (Coxsackie B and Echo) and its relationships with human leukocyte antigen (HLA) class II alleles, TLR expression (monocytes), serum cytokine profile and islet beta cell autoantibodies in 51 individuals (40 T1D and 11 non-affected siblings) from 20 T1D multiplex-sib families and 54 healthy control subjects. The viral antibody profiles were similar among all groups, except for antibodies against CVB2, which were more prevalent in the non-affected siblings. TLR4 expression was higher in the T1D multiplex-sib family's members than in the control subjects. TLR4 expression showed a positive correlation with CBV2 antibody prevalence (rS: 0.45; P = 0.03), CXCL8 (rS: 0.65, P = 0.002) and TNF-alpha (rS: 0.5, P = 0.01) serum levels in both groups of T1D multiplex-sib family. Furthermore, within these families, there was a positive correlation between HLA class II alleles associated with high risk for T1D and insulinoma-associated protein 2 autoantibody (IA-2A) positivity (odds ratio: 38.8; P = 0.021). However, the HLA protective haplotypes against T1D prevalence was higher in the non-affected than the affected siblings. This study shows that although the prevalence of viral infection is similar among healthy individuals and members from the T1D multiplex-sib families, the innate immune response is higher in the affected and in the non-affected siblings from these families than in the healthy controls. However, autoimmunity against beta-islet cells and an absence of protective HLA alleles were only observed in the T1D multiplex-sib members with clinical disease, supporting the importance of the genetic background in the development of T1D and heterogeneity of the interaction between environmental factors and disease pathogenesis despite the high genetic diversity of the Brazilian population. CI - Copyright (c) 2020 Bergamin, Perez-Hurtado, Oliveira, Gabbay, Piveta, Bittencourt, Russo, Carmona, Sato and Dib. FAU - Bergamin, Carla Sanchez AU - Bergamin CS AD - Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de Sao Paulo, Sao Paulo, Brazil. FAU - Perez-Hurtado, Elizabeth AU - Perez-Hurtado E AD - Immunology Division, Microbiology, Immunology and Parasitological Department, Escola Paulista de Medicina - Universidade Federal de Sao Paulo, Sao Paulo, Brazil. FAU - Oliveira, Luanda AU - Oliveira L AD - Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology and Tropical Medicine Institute of Sao Paulo, Faculdade de Medicina - Universidade de Sao Paulo, Sao Paulo, Brazil. FAU - Gabbay, Monica AU - Gabbay M AD - Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de Sao Paulo, Sao Paulo, Brazil. FAU - Piveta, Valdecira AU - Piveta V AD - Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de Sao Paulo, Sao Paulo, Brazil. FAU - Bittencourt, Celia AU - Bittencourt C AD - Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de Sao Paulo, Sao Paulo, Brazil. FAU - Russo, Denise AU - Russo D AD - Enteric Diseases Laboratory, Virology Center From Instituto Adolfo Lutz, Sao Paulo, Brazil. FAU - Carmona, Rita de Cassia AU - Carmona RC AD - Enteric Diseases Laboratory, Virology Center From Instituto Adolfo Lutz, Sao Paulo, Brazil. FAU - Sato, Maria AU - Sato M AD - Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology and Tropical Medicine Institute of Sao Paulo, Faculdade de Medicina - Universidade de Sao Paulo, Sao Paulo, Brazil. FAU - Dib, Sergio A AU - Dib SA AD - Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de Sao Paulo, Sao Paulo, Brazil. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200923 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 0 (Antibodies, Neutralizing) RN - 0 (Antibodies, Viral) RN - 0 (Autoantibodies) RN - 0 (HLA Antigens) RN - 0 (Interleukins) RN - 0 (Toll-Like Receptors) RN - 0 (islet cell antibody) SB - IM MH - Adolescent MH - Adult MH - Alleles MH - Antibodies, Neutralizing/*blood MH - Antibodies, Viral/*blood MH - Autoantibodies/blood MH - Cross-Sectional Studies MH - Diabetes Mellitus, Type 1/genetics/*immunology MH - Enterovirus/*immunology MH - Female MH - HLA Antigens/*genetics MH - Haplotypes MH - Humans MH - Immunity, Innate MH - Interleukins/analysis MH - Male MH - Monocytes/*immunology MH - Siblings MH - Toll-Like Receptors/*analysis MH - Young Adult PMC - PMC7538605 OTO - NOTNLM OT - HLA class II OT - coxsackievirus OT - innate immunity OT - islet-cell autoimmunity OT - multiplex families OT - toll-like receptors OT - type 1 diabetes EDAT- 2020/10/20 06:00 MHDA- 2021/05/27 06:00 PMCR- 2020/01/01 CRDT- 2020/10/19 05:55 PHST- 2020/04/25 00:00 [received] PHST- 2020/08/14 00:00 [accepted] PHST- 2020/10/19 05:55 [entrez] PHST- 2020/10/20 06:00 [pubmed] PHST- 2021/05/27 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fendo.2020.555685 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2020 Sep 23;11:555685. doi: 10.3389/fendo.2020.555685. eCollection 2020.