Jorge Kalil

Autoimmunity in Chagas' Disease

Chronic Chagas Disease Cardiomyopathy (CCC) is one of the few well-defined examples of human post-infectious autoimmunity, as documented by several groups in over 50 publications. The time scale dissociation between primary infection with high tissue and blood parasitism and tissue pathology, allied to the scarcity of T. cruzi in CCC heart lesions prompted investigators as early as 70 years ago to suggest that the mononuclear cell infiltrate should directly damage the heart in an autoimmune fashion. This chapter discusses evidence for autoimmunity as a major factor for heart tissue damage in CCC. Unraveling the mechanism by which an infectious agent can trigger organ-specific autoimmunity may lead to reverse strategies for identifying putative triggering infectious agents in autoimmune diseases of suspected infectious etiology. In addition, testing current concepts on molecular pathogenesis of human autoimmune disorders on proven post-infectious autoimmune disease like CCC and rheumatic fever may allow the early identification of susceptible individuals and therapy of affected patients.

Distinct Mitral Valve Proteomic Profiles in Rheumatic Heart Disease and Myxomatous Degeneration

Rheumatic heart disease (RHD) affects heart-valve tissue and is the most serious consequence of group A Streptococcus infection. Myxomatous degeneration (MXD) is the most frequent valvopathy in the western world. In the present work, key protein expression alterations in the heart-valve tissue of RHD and MXD patients were identified and characterized, with controls from cadaveric organ donors. Proteins were separated by two-dimensional (2D)-electrophoresis and identified by mass spectrometry. We found 17 differentially expressed protein spots, as compared to control samples. We observed an increased expression of ASAP-2 in the RHD patients’ valves, while collagen-VI, haptoglobin-related protein, prolargin, and cartilage oligomeric protein showed reduced expression. Valve tissue of MXD patients, on the other hand, presented lower expression of annexin-Al and A2, septin-2, SOD (Cu/Zn), and transgelin. Tissue samples from both valvopathies displayed higher expression of apolipoprotein-Al. Biglycan was downexpressed in both diseases. Vimentin and lumican showed higher expression in RHD and lower in MXD. These results suggest that key pathogenetic mechanisms are intrinsically distinct in RHD and MXD.

Autoreactivity to self H-2Kb peptides in TAP1−/− mice. Intravenous administration of H-2Kb class I-derived peptides induces long-term survival of grafts from C57BL/6 donors

We and others have previously shown that TAP1–/– mice (H‐2b) reject grafts from donors without major histocompatibility complex (MHC) disparity that express wild‐type levels of H‐2b class I molecules (C57BL/6, TAP1+/+ mice). In this same model, we also showed that subcutaneous priming of TAP1–/– mice with synthetic peptides derived from the H‐2Kb molecule accelerated graft rejection and that in vivo depletion of CD4+ T cells induced a significant prolongation of graft survival, suggesting an important role for CD4 T cells. We hypothesize that, in this model, rejection is triggered by the recognition of class I molecules or derived peptides, in an inflammatory microenvironment, by a functionally altered autoreactive T‐cell repertoire that escapes the control of peripheral regulatory mechanisms. In the present study, we analysed the cellular autoreactivity induced by synthetic peptides derived from the H‐2Kb sequence in naive and TAP1–/– mice transplanted with C57BL/6 grafts, and investigated whether intravenous modulation of autoreactivity to these peptides induced transplantation tolerance. We showed that TAP1–/– mice have peripheral autoreactive T cells that recognize H‐2Kb peptides. A significant amplification of proliferation against these peptides was detected in TAP1–/– mice that rejected grafts, indicating that the inflammatory context of transplantation induced peripheral expansion of these autoreactive T cells. Furthermore, intravenous injection of H‐2Kb‐derived peptides significantly prolonged graft survival in some animals. In these mice (>u2003100u2003days graft survival), we observed intragraft inhibition of interferon‐γ and interleukin‐10 expression, suggesting that these cytokines have an active role during the rejection. In conclusion, our present data indicate that inflammatory autoreactive T cells directed against H‐2Kb peptides can be inhibited in the periphery to prolong graft survival in TAP1–/– mice.

Endomiocardite de Loeffler – manifestação cardíaca da síndrome hipereosinofílica: relato de caso

RESUMO 1. Hospital das Clínicas Faculdade de Medicina da Universidade de São Paulo, Serviço de Imunologia Clínica e Alergia São Paulo, SP, Brasil. 148 Introdução: A síndrome hipereosinofílica é caracterizada por uma produção aumentada e contínua de eosinófilos e pode levar a lesões teciduais em múltiplos órgãos, como consequência da infiltração eosinofílica. Os pacientes apresentam eosinofilia absoluta no sangue periférico (> 1.500 eosinófilos/mm3) sem uma causa primária de eosinofilia. A manifestação cardíaca desta síndrome geralmente se apresenta como endomiocardite de Loeffler, que constitui uma miocardiopatia restritiva primária resultante da infiltração de eosinófilos no tecido cardíaco. Descrição do caso: Relatamos o caso raro de uma paciente de 64 anos com eosinofilia a esclarecer e comprometimento cardíaco, que teve o diagnóstico estabelecido a partir de exames de imagem. Comentários: Enfatizamos os aspectos clínicos e evolutivos, ressaltando as dificuldades diagnósticas e a importância da investigação de eosinofilias persistentes sem causa aparente, uma vez que o diagnóstico e tratamento precoce podem proporcionar melhores taxas de sobrevida e prognóstico nestes pacientes. Descritores: Síndrome hipereosinofílica, endocardite, diagnóstico. Introduction: The hypereosinophilic syndrome is characterized by an increased, continuous production of eosinophils, and it may lead to tissue damage in multiple organs as a consequence of eosinophilic infiltration. Patients with this syndrome present absolute eosinophil count > 1,500 eosinophils/mm3 in the peripheral blood without a primary cause for eosinophilia. The cardiac manifestation of this syndrome usually presents as Loeffler’s endomyocarditis, a primary restrictive cardiomyopathy resulting from the infiltration of eosinophils into cardiac tissue. Case description: We report the rare case of a 64-year-old woman with eosinophilia and cardiac involvement, who had the diagnosis established based on imaging tests. Comments: We emphasize the clinical and evolutionary aspects of the condition, highlighting the diagnostic difficulties and the importance of investigating persistent eosinophilia without an apparent cause, as early diagnosis and treatment can provide better survival rates and improved prognosis in these patients.