* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Slide 1
Survey
Document related concepts
Lymphopoiesis wikipedia , lookup
DNA vaccination wikipedia , lookup
Molecular mimicry wikipedia , lookup
Immune system wikipedia , lookup
Adaptive immune system wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Human cytomegalovirus wikipedia , lookup
Pathophysiology of multiple sclerosis wikipedia , lookup
Hepatitis B wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Innate immune system wikipedia , lookup
Sjögren syndrome wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Transcript
Immunology and Infection in Chronic Fatigue Syndrome Nancy Klimas, MD UNIVERSITY OF Miami SCHOOL OF MEDICINE Model of CFS Pathogenesis Genetic Predisposition Triggering event / infection Mediators (Immune, endocrine, neuroendocrine, psychosocial, viral reactivation or persistence) CFS/ME Genetic Predisposition - CFS HLA DR haplotypes in 112 South Florida CFS patients, compared to 5,000 regional and national controls 4 to 6 fold increased relative risk for DR4, DR3 and DQ3. (Keller et al, 1992) Seattle CFS Cooperative Research Center Twin study - genetic predisposition, hereditability estimate of 51% (2nd World Conf); similar results in Sweden, Australian studies Evidence for Triggering event/ infection - CFS 60 to 80% of CFS subjects onset an acute virallike illness (Komaroff, Buchwald) Less so in population based studies. (Reeves, Jason) Andrew Lloyd and colleagues in Australia performed a prospective study - anergy during acute infection predicted persistent CFS like symptoms Severity of initial infection single best predictor Model of CFS Pathogenesis Genetic Predisposition Triggering event / infection Mediators (Immune, endocrine, neuroendocrine, psychosocial, viral reactivation or persistence) CFS/ME CRF CNS Symptoms • Altered perceptions - fatigue - pain • Cognitive changes - concentration - memory • Mood alterations - depression - anxiety • Sleep disturbances - unrefreshing sleep - altered sleep-wake cycle Physical stress activates immune system and HPA axis Emotional stress activates immune system and HPA axis Hypothalamic-PituitaryAdrenal Axis • Relative Hypocortisolemia Musculoskeletal System • Myalgia & Arthralgia Gastrointestinal Tract • Altered bowel habits • Abdominal pain Heart and Blood Vessels • Altered blood pressure responses • Dizziness Immune System • Lymph node tenderness • Sore throat • Enhanced Cytokines Video link: The leukocyte . http://www.studiodaily.com/main/searchlist/6850.html http://multimedia.mcb.harvard.edu/media.html Immune cascade Macrophage presents antigen Natural Killer Cells(Th1) Helper CD4 cell Th1 cytokines IL-2, INF activates CD8 . Helper CD4 cell Th2 cytokines IL-6, IL-10 activates B cells CD8 cells kill virus B cells make antibody prevent and help clear infection Immune abnormalities in CFS Immune Activation DR, CD26 expression TH2 cytokine shift Proinflammatory cytokines expression TNF-a, IL-1, IL6 Functional defects NK Cell dysfunction CD8 abnormalities perforins, granzymes Macrophage abnormalities Antibody production Photo by Leventhal, Karnovsky and Martz NK Cytotoxicity: % K562 Cells Killed at Target to Effector Cell Ratio of 1:1 40 35 30 25 GWI 20 CFS 15 Controls 10 5 0 Subjects Natural Killer Cell Perforin is a molecule in cytotoxic lymphocytes necessary for killing of virus infected and tumor cells. Cell Surface Antigen: CD56 Intracellular Cytolytic Granules: * Perforin * Granzyme A * Granzyme B Natural killer (NK) cell cytolytic capacity was measured by quantitative flow cytometry of intracellular content of perforin, with data expressed as relative number of molecules of perforin per CD3CD56+ lymphocyte (rMolPer/NK cell). Intracellular Perforin 7000 6000 5000 4000 GWI 3000 CFS Controls 2000 1000 0 Subjects 8000 Perforin p = 0.01 rMolecules / NK Cell p = 0.05 6000 4000 2000 0 Lo NKCC Hi NKCC CFS Controls Subject Groups Perforin 2000 p = 0.01 p = 0.01 rMolecules / CD3+CD8+ Cell 1600 1200 800 400 0 Lo NKCC Hi NKCC CFS Controls Subject Groups CD26 (dipeptidyl peptidase IV) is involved in the activation of T cells, and is expressed on antigen-reactive memory T cells. As reported by the Miami CFS research group, the percentage and number of CD26+ lymphocytes is elevated in CFS. Lymphocyte Activation in GWI and CFS: Percent of CD2+CD26+ Lymphocytes 70 60 50 40 GWI 30 CFS Controls 20 10 0 Subjects Qualitative flow cytometry showed fewer numbers of molecules of DPPIV/CD26 on T and NK cells in CFS patients. 8000 6000 Molecules of CD26 on T Cells p < 0.0002 4000 2000 0 Controls CFS Neuropeptide-Y (NPY) is peptide,which participates in the regulation of a large number of physiological and pathophysiological processes in the cardiorespiratory system, immune system, nervous system and endocrine system. NPY is stored in sympathetic nerve terminals and is released along with catecholamines during stressinduced activation. Only a few peptidases are capable of cleaving NPY due to its unique 3-diminsional structure. DPPIV/CD26 is one such peptidase. In the GWI patients, we found a reduced amount of NPY in plasma. BIOMARKER NPY (pmol/L) GWI 37* CFS 41 *Significantly different from HC (p<.05) HC 52 LYMPHOCYTE PROLIFERATION IN RESPONSE TO PHA: MEAN (+/- S.D.) NET CPM . IN CFS PATIENTS ABOVE OR BELOW THE MEAN ON COGNITIVE DIFFICULTIES SCALE . .. 210000 180000 150000 120000 P = .O3 90000 60000 30000 LOW CDS HIGH CDS Medical Outcomes Survey Short Form-36 ( SF-36) Women with CFS 80 Group Means (+/- SD) • . . • . 65 p = .003 50 35 20 5 LOW NKCC N = 22 NORMAL NKCC N = 19 SF-36 measures the impact of illness including limitations due to physical health, pain, vitality, social functioning, emotional problems and general mental health. Paced Auditory Serial Addition Task (PASAT) Women with CFS 55 p = <.001 41 28 14 Group Means (+/- SD) Low NKCC n = 22 0 Normal NKCC n = 19 The PASAT is an objective measure of: rate of information processing, sustained attention and divided attention Immune –Endocrine Link IL-6 increase associates with low cortisol, CRH mediated Papanicolau Neuroimmunomodulation 2004 11(2)65-74 Maes M Neuro Endocrinol Lett 2005 Oct 30;26(5) Viral Persistence/Reactivation HHV6 virus is present in 22 to 54% of patients in cross sectional studies (Ablashi, Krueger, Knox), HHV6 virus is present in 79% of CFS patients in longitudinal studies (HHV6 PCR assay, Knox) HHV6 virus is present in the spinal fluid of 28 of 120 CFS patients (Peterson), and 7 of 35 CFS samples (Knox). Enterovirus is present in 13% of CFS muscle samples (Douche-Aourik, 2003); EBV – dUTPase as a immune modulator, up regulating inflammatory cytokines (Glaser, 2005) (Glaser et al Brain Behavior and Immunity 2005 19(2):91-103) Viral and Immune Interactions and Health J Chia showed GI biopsies with enterovirus inclusions, found in patients with CFS and abdominal complaints Novel mechanisms of virus mediated chronicity Glaser et al found evidence of regulatory peptides encoded by EBV expressed in CFS despite the absence of replicative virus These peptides are known to modulate immune function, inducing pro-inflammatory and Type 2 cytokines Lerner’s group found evidence of a subgroup of CFS patients with incomplete viral expression and cardiac motility abnormalities; subset of CFS with 2 Lerner M etEBV al In Vivo 2004(18) 4:417; (18)2:101 IgM 3 Glaser R Brain Behavior Immun 2005 19(2):91 Treating HHV6a? Association vs. causation Blood PCR HHV6 a did not predict HHV6 virus is present in the spinal fluid CSF did not predict blood Of 120 CSF samples, 44 had abnormalities of protein, glucose or cells. Of the 44 , 28 were positive for HHV6(26), EBV (1), or CMV(1). 5 of 8 CSF PCR positive treated until CSF cleared returned to full time employment (Peterson); in his experience TK inhibitors did not clear CSF, patients required foscarnet or cidofovir Open label valgancyclovir 20 of 23 responders in high titer EBV plus HHV6 selected cohort , (Jose Montoya) Placebo control trials have not been completed Clinical Trials M Lerner reported a phase 1 trial of valgangciclovir in CFS patients with evidence of cardiac dysfunction. 37 patients were treated in an open label study, with improvement in all 37. He emphasized the need to hydrate, monitor renal and liver function. Genomics, Proteomics, and Viral Chips IACFS Conf 2007 : Inflammation pathways, IL-6, TNFa upregulated in a subgroup, suggesting monoconal ab blockers as a treatment (Kerr, Vernon, Olano) CFS proteome (Baruniuk) Serum analysis using infrared spectroscopy (Sakudo, Watanabe, Ikuta, Kuratsune) 28 potential microbes under study (Kerr) Reno research group using viral chip technology in CFS and CFS associated malignancy Conclusion Immune dysfunction in CFS contributes to the overall symptom complex, and contributes to the persistence of the illness, both directly and through interaction with neuropeptides and hormones. There is increasing evidence of viral reactivation in at least a subset of the patient population. Interventive trials are currently focused on HHV6 virus. This work is helping to identify subgroups of CFS patients, identifying biomarkers, and potential treatment options. Thank You! Immunology/Virology: Drs. Mary Ann Fletcher, Kevin Maher, Roberto Patarca Autonomic: Dr. Barry Hurwitz Health Assessment: Drs. Michael Antoni, Mary Catherine Segota, Jackie Junco Professional links: IACFS/ME on line: www.iacfs.net CDC on line: www.cdc.gov NIH on line: www.nih.gov Photo by Leventhal, Karnovsky and Martz