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Postgraduate Program in Neurology Postgraduate Program in Genetics and Molecular Biology

Federal University of the Sate of Rio de Janeiro. Postgraduate Program in Neurology Postgraduate Program in Genetics and Molecular Biology. Functional profile of T cells of patients suffering from immune disturbances: AIDS and autoimmune diseases. Instituto Biomédico.

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Postgraduate Program in Neurology Postgraduate Program in Genetics and Molecular Biology

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  1. Federal University of the Sate of Rio de Janeiro Postgraduate Program in Neurology Postgraduate Program in Genetics and Molecular Biology Functional profile of T cells of patients suffering from immune disturbances: AIDS and autoimmune diseases Instituto Biomédico Dr. Cleonice Alves de Melo Bento Associate Professor of Immunology Lab. Immunophysiology and Immunopathology of T cells

  2. Theimmune system The invaders The defenders M. tuberculosis x C. neoformans T. cruzi HIV N. meningitidis S. mansoni S. Jorge, Lisboa

  3. FEDERAL UNIVERSITY OF RIO DE JANEIRO STATE The HIV-1- infection in immunologically special patients: pregnant women and elderly Dr. Cleonice Alves de Melo Bento Professor of Immunology Department of Microbiology and Immunology Lab. Immunophysiology and Immunopathology of T Lymphocytes

  4. Course of HIV infection

  5. Anorexia • Letargia • Apatia • Fadiga • Alterações de sono/vigília • Dificuldades de aprendizado e memória • Perda de interesse para o convívio social • Ativação HPA em hipotálamo -> cortisol e catecol, inibidores da imunidade celular. HIV infection and AIDS Viral replication Hyperactivation

  6. Chronic immune activation and HIV disease pthogenesis: a hypothesis  Inflammatory cytokines • CD38+CCR5+ T cells • CD27-CD57+ T cells • Fas+PD-1+Tim-3+ CTLA-4 T cells  Treg cells • Thymopoiesis  Stress homones  PAMPs (LPS, bDNA) T CD8T  Mibrobial translocation CD4T sCD4T sCD8T NKT Breakdown of local immune and epithelial cells Dramatic loss of CCR5+ CD4+ Tcells (Classical CD4+T H17+ cells, iNKTcells, Treg cells)  Viral replication

  7. Anti-retroviral therapy (ARV) and immune recovery • Control of virus replication • Increase in peripheral CD4+ T cell counts • Elevation in the frequency of naïve and central memory T cell • Decrease in the frequency of dysfunctional T (CD38, HLA-DR, CD95, PD-1, CTLA-4) • Deficient functional HIV-1-specific CD4 T cells recovery Response to HAART Blood 2006; 108:3072–3078 AIDS 2008, 22:439–446

  8. Aging of the HIV infection epidemic Evolution of the incidence of AIDS in Brazil according to the age from 1998 to 2008.

  9. Ageing: Immunesenescence (immunehyperactivation)

  10. HIV infection in the elderly • Fasterdiseaseprogressionthanyoungpatients • Poor CD4+ T cellrecovery in treatedpatients • Excelent virological response • AIDS 2004, 18:2029-2038 • J AntimicrobChemother 2006, 57: 4–7 • Aging health 2008, 4(6): 615–627 • J AmGeriatrSoc 2009, 57(11): 2129-38

  11. The role of interleukin 10 (IL-10) produced by CD4+ T cells from 16 aged patients on in vitro HIV-1 replication and cytokine production.

  12. CD45RA+CD62L+ CD45RO+CD127+ CD45RO+CD127- HIV-1 infection in older AIDS patients elevates the frequency of Tr-1 cells. HAART did not recovery the frequency of naive and central memory in CD4+ T cells from elderly HIV-infected subjects.

  13. CD45RA+CD62L+ CD45RO+CD127+ CD45RO+CD127- Effector Central memory CD4+ T cells Naïve wks wks HAART treatment HAART did not recovery the frequency of naive and central memory in CD4+ T cells from elderly HIV-infected subjects. Dinamic of CD4 T cells recovery following HAART treatment (Wilkinson et al., 2009).

  14. JAIDS, 2010;54(1):10-7 Lower IgG anti-Tetanus toxin (TT) in successfully HAART-treated older AIDS patients.

  15. CLINICAL UNSOLVED ISSUES • Should we start prophylaxis for opportunistic infections earlier for aged patients ? • Can we interrupt the prophylaxis for opportunistic infections at the same levels of CD4 cell counts as we do for young patients ? • Should we start antiretroviral therapy earlier for aged patients ? • Should we use the same vaccination strategies recommended for all AIDS patients?

  16. HIV and pregnancy

  17. HIV infection in pregnant women • Goodcontrolof viral loadduringpregnancy • Virologicreboundafterdelivery • Pregnancy is not a riskfactor for fasterclinicalprogression • JAIDS 2003, 33(5):585-93 • RevBrasGinecolObstet 2005, 27(7):393-400 • J AntimicrobChemother 2006, 57: 4–7

  18. A successful pregnancy depends on an immunological tolerance state to the fetal allograft, coordinated by maternal regulatory T cells . Th17/ /Th17 Hum Reprod Update 2009, 15(5): 517–535 Am J Reprod Immunol 2010, 63:601-610. J Reprod Immunol 2010; 84:164-170.

  19. David Klatzmann Pitié-Salpêtrière/Paris

  20. HIV-1-Exposed non-infected neonates

  21. “FUNCTIONAL ANALISYS OF T CELLS OF PATIENTS SUFFERING FROM IMMUNODEFICIENCIES” Instituto de Medicina Molecular (IMM) Faculdade de Medicina Hospital Santa Maria Universidade de Lisboa

  22. Clinical Immunology Lab Ana E. Sousa Espada, MD, PhD

  23. Ana E Sousa team “The impact of pregnancy in modulating broadly neutralizing HIV antibody responses” • IL-7 and naive T cell homeostasis • Regulatory T cells • development and induction • HIV / AIDS immunopathogenesis • HIV-2 • Primary Immunodeficiencies • Centro HSM/FMUL/IMM • Immunoallergology

  24. Federal University of the Sate of Rio de Janeiro Postgraduate Program in Neurology The immunopathological profile of multiple sclerosis and neuromyelitis optica Dr. Cleonice Alves de Melo Bento Associate Professor of Immunology Lab. Immunophysiology and Immunopathology of T cells

  25. Multiple sclerosis (MS)and neuromyelitis optica (NMO):autoimmune attack of the myelin sheath of central nervous system . MS: brain, optic nerves and spinal cord. NMO: optica nerves and spinal cord. http://www.mayoclinic.com/health/medical/IM01480

  26. Expanded disability status scale (EDSS) http://www.mobilitymattersinms.com/site/assessment-tests.aspx

  27. Immunopatologyof MS Experimental autoimmune encephalomyelitis (EAE): myelin-specific T cells Hemmer, Archelos & Hartung, 2002 MAG: myelin-associated glycoprotein; MBP: myelin basic protein; MOG: myelin oligodendrocyte glycoprotein; PLP: proteolipid protein.

  28. Th1/Th17 axis in MS mDC Neutrophils Defensins β, ROS, NO IL-1β IL-6 IL-23 Naïve CD4+ T cell IL-6R Macrophages IL-8 IL-1R IL-23R Proliferation Mucus production Reg3, lipocalin-2, ocludin Epithelial cells CD4+CCR6+ CD161+ T cells Th1 cells IL-17A (IL-17) IL-17F IL-21 IL-22 CCL20 STAT-3 ROR-t ROR-α Y Y Y Y Y Y Y Y Y Y Plasma cells Neutrophils Glial cells IFN- IL-2 Chemoattraction of Th17 cells MMP (Tissue damage) Macrophages CD8+ CTL

  29. The IL-17 production is related with neurological disorders and HC-sensitivity in MS patients.

  30. In vivo LPS quantification and its relationship with cytokine production and neurological disability.

  31. Dopamine and Th17 Dopamine IL-17 IL-22 IL-1β TNF-α Th17 GCs Chronic stress Regulatory T cells IL-10 TGF- nTreg Tr-1 Adrenal glands

  32. Dopamine favors expansion of glucocorticoid-resistant IL-17-producing T cells in multiple sclerosis. Thais B. Ferreiraa*, Priscila O. Barrosa*; Bruna Teixeiraa, Vera Carolina B. Bittencourta, Taissa M. Kasaharaa, Joana Hyginoa, Claudia Cristina F. Vasconcelosb, Helcio Alvarenga Filhob, Regina Alvarengab, Ana Cristina Wingb, Regis M. Andradec, Arnaldo F. Andraded, and Cleonice A. M. Bentoa,b From aDepartment of Microbiology and Parasitology, bPost-graduate Program in Neurology and cDepartment of General Medicine / Federal University of the State of Rio de Janeiro and dDepartment of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil; Submitted to Multiple sclerosis

  33. Th17-related cytokines and NMO • Elevated levels of IL-6 and IL-8 in the CSF associated with high IL-6 in the plasma (Uzawa et al., 2010; 16: 1443-1452). • The IL-17/IL-8 axis was directly related to NMO lesions during clinical relapses The level of IL-8 was dirctly related to neutrophilia and medulary lesions (Takaaki et al., Brain, 2005; 128:988-1002).

  34. Blood-brain barrier Microglial and neuromal processes (TGF-, BDNF) _ (TGF-, angiogenesis, clearance of toxic molecules) _ _ Fig. 1. Cellular structure of the BBB. Endothelial cells have luminal tight junctions and form the capillary and the barrier. There is a basement membrane that surrounds the pericyte and astrocyte outside endothelial cells. Astrocytic end feet are in close proximity to all of these structures. Takeshita & Ransohoff, Immonol Rev, 2012; 248:228

  35. NMO as humoral –based autoimmune IgG1 anti-AQP4 titers: associated with severity of cord spinal lesions and also predictive of relapses Immune complex: IgM/IgG1 + C9 C5a CXCL1 CXCL2 Bento, CAM

  36. The relationship between in vitro IL-6 and IL-21 production and EDSS score in NMO patients

  37. Are Tfh cells an appropriate new target in the treatment of NMO?

  38. The role of IgG antii-AQP4 in the NMO pathogenesis Dr. Romain Maringnier Lyon University Priscila O. Barros PhD Student The Tfh cell behavior in humoralantoimmune diseases Priscila O. Barros Post-Doc Student Dr. Michelle Rosenzwajg Pitié Salpêtrière/Paris

  39. Programa de Professor/Pesquisador Visitante nos EUA (Capes/Comissão Fulbright) Title of Project “The effect of TLR activation on ability of corticoid in inhibiting human T cell activation” Sudhir Gupta Professor of Medicine, Pathology & Laboratory Medicine, and Microbiology & Molecular Genetics, MedicineSchool of Medicine California University, USA Cleonice A. M. Bento Professor of Immunology UNIRIO/ BR

  40. Dr. Amilcar Tanuri/UFRJ Dr. Arnaldo Andrade/UERJ Support:

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