Peripheral imbalanced TFH/TFR ratio correlates with intrathecal IgG synthesis in multiple sclerosis at clinical onset

Background: Alteration of T-follicular helper (TFH) and regulatory (TFR) subpopulations may contribute to the development of auto-reactive B-cell. Objective: To investigate whether changes in TFH and TFR subsets are associated with abnormal IgG synthesis in blood and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. Methods: Paired blood and CSF samples were obtained from 31 untreated relapsing-remitting multiple sclerosis (RRMS) patients at diagnosis. Peripheral blood TFH (CD3+CD4+CXCR5+CD25–CD127+), TFR (CD3+CD4+CXCR5+CD25+CD127dim), conventional T-Helper (TH, CD3+CD4+CXCR5–CD25–CD127+), and regulatory T-cells (T-Reg, CD3+CD4+CXCR5–CD25+CD127dim) were analyzed in all RRMS patients and in 13 healthy controls (HCs). Qualitative and quantitative intrathecal IgG synthesis was evaluated in RRMS patients, who were then further subclassified according to the presence of IgG oligoclonal bands in blood and/or CSF. Results: Compared to HC, RRMS had lower TFR percentage (p < 0.01) and higher TFH/TFR ratio (p < 0.001). In RRMS, TFH/TFR ratio correlated with both qualitative (r = 0.56, p < 0.005) and quantitative intrathecal IgG synthesis (IgG Index: r = 0.78; IgGLoc: r = 0.79; IgGIF: r = 0.76, all p < 0.001). Patients with the highest TFH/TFR ratios had higher percentages of circulating B-cells (36.1 ± 35.2%, p < 0.05). Conclusion: In RRMS, increased TFH/TFR ratio associates with abnormal IgG production in blood and CSF, suggesting that antibody-producing cells, derived from deregulated peripheral germinal center reaction, colonize the CNS.

[1]  P. Gallo,et al.  Evidence of B-cell dysregulation in severe CNS inflammation after alemtuzumab therapy , 2017, Neurology: Neuroimmunology & Neuroinflammation.

[2]  T. Marquez-Lago,et al.  Dynamic regulation of T Follicular Regulatory cell responses by interleukin 2 during influenza infection , 2017, Nature Immunology.

[3]  A. E. Sousa,et al.  Human blood Tfr cells are indicators of ongoing humoral activity not fully licensed with suppressive function , 2017, Science Immunology.

[4]  L. Graça,et al.  T follicular regulatory cells in mice and men , 2017, Immunology.

[5]  A. Traboulsee,et al.  Ocrelizumab versus Interferon Beta‐1a in Relapsing Multiple Sclerosis , 2017, The New England journal of medicine.

[6]  Bernhard Hemmer,et al.  Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis , 2017, The New England journal of medicine.

[7]  H. Wekerle B cells in multiple sclerosis , 2017, Autoimmunity.

[8]  A. DeFranco The germinal center antibody response in health and disease , 2016, F1000Research.

[9]  I. Maclennan,et al.  Follicular Helper T Cells. , 2016, Annual review of immunology.

[10]  A. Sharpe,et al.  T follicular regulatory cells , 2016, Immunological reviews.

[11]  G. Papp,et al.  A comprehensive investigation on the distribution of circulating follicular T helper cells and B cell subsets in primary Sjögren's syndrome and systemic lupus erythematosus , 2016, Clinical and experimental immunology.

[12]  M. Hecker,et al.  Molecular biomarkers in cerebrospinal fluid of multiple sclerosis patients. , 2015, Autoimmunity reviews.

[13]  N. Hellings,et al.  Circulating Follicular Regulatory T Cells Are Defective in Multiple Sclerosis , 2015, The Journal of Immunology.

[14]  T. Jin,et al.  Circulating CCR7+ICOS+ Memory T Follicular Helper Cells in Patients with Multiple Sclerosis , 2015, PloS one.

[15]  S. Crotty A brief history of T cell help to B cells , 2015, Nature Reviews Immunology.

[16]  U. Klein,et al.  Dynamics of B cells in germinal centres , 2015, Nature Reviews Immunology.

[17]  Philip D. Hodgkin,et al.  The generation of antibody-secreting plasma cells , 2015, Nature Reviews Immunology.

[18]  L. Ma,et al.  High frequencies of activated B cells and T follicular helper cells are correlated with disease activity in patients with new‐onset rheumatoid arthritis , 2013, Clinical and experimental immunology.

[19]  H. D. de Vries,et al.  Grey matter damage in multiple sclerosis , 2013, Prion.

[20]  R. Reynolds,et al.  Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis. , 2012, Brain : a journal of neurology.

[21]  V. Kuchroo,et al.  Immune checkpoints in central nervous system autoimmunity , 2012, Immunological reviews.

[22]  J. Craft Follicular helper T cells in immunity and systemic autoimmunity , 2012, Nature Reviews Rheumatology.

[23]  J. Craft,et al.  T cells that promote B‐Cell maturation in systemic autoimmunity , 2012, Immunological reviews.

[24]  B. Scheithauer,et al.  Inflammatory cortical demyelination in early multiple sclerosis. , 2011, The New England journal of medicine.

[25]  R. Reynolds,et al.  Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. , 2011, Brain : a journal of neurology.

[26]  Jeffrey A. Cohen,et al.  Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria , 2011, Annals of neurology.

[27]  R. Reynolds,et al.  A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis , 2010, Annals of neurology.

[28]  E. Frohman,et al.  Multiple sclerosis--the plaque and its pathogenesis. , 2006, The New England journal of medicine.

[29]  Hansotto Reiber,et al.  Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs , 2001, Journal of the Neurological Sciences.

[30]  Moses Rodriguez,et al.  Distinct Patterns of Multiple Sclerosis Pathology Indicates Heterogeneity in Pathogenesis , 1996, Brain pathology.

[31]  E. Thompson,et al.  Serum oligoclonal IgG is a common and persistent finding in multiple sclerosis, and has a systemic source. , 1996, QJM : monthly journal of the Association of Physicians.

[32]  G. Bernardi,et al.  Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. , 1994, Journal of neurology, neurosurgery, and psychiatry.

[33]  W. Tourtellotte,et al.  Temporal invariance and clonal uniformity of brain and cerebrospinal IgG, IgA, and IgM in multiple sclerosis , 1986, The Journal of experimental medicine.

[34]  I A Mjör,et al.  Consensus Report , 1985, Journal of dental research.

[35]  T. Olsson,et al.  Improved detection of oligoclonal IgG in cerebrospinal fluid by isoelectric focusing in agarose, double-antibody peroxidase labeling, and avidin-biotin amplification. , 1984, Clinical chemistry.

[36]  G. Tibbling,et al.  Principles of albumin and IgG analyses in neurological disorders. III. Evaluation of IgG synthesis within the central nervous system in multiple sclerosis. , 1977, Scandinavian journal of clinical and laboratory investigation.