B cells and immunosenescence: A focus on IgG+IgD−CD27− (DN) B cells in aged humans

Ademokun, 2010, The ageing B cell population: composition and function, Biogerontology, 11, 125, 10.1007/s10522-009-9256-9 Agematsu, 2000, CD27: a memory B-cell marker, Immunol. Today, 21, 204, 10.1016/S0167-5699(00)01605-4 Agrawal, 2010, TLR1/2, TLR7, and TLR9 signals directly activate peripheral blood naive and memory B cell subsets to produce cytokines, chemokines, and hematopoietic growth factors, J. Clin. Immunol. Akbar, 2005, Memory T cell homeostasis and senescence during ageing, Curr. Opin. Immunol., 17, 480, 10.1016/j.coi.2005.07.019 Almanzar, 2004, IFN-gamma production by CMV-specific CD8+ T cells is high in elderly donors, Exp. Gerontol., 39, 863, 10.1016/j.exger.2004.01.017 Alter-Wolf, 2009, Deviation of the B cell pathway in senescent mice is associated with reduced surrogate light chain expression and altered immature B cell generation, phenotype, and light chain expression, J. Immunol., 1, 138, 10.4049/jimmunol.182.1.138 Alter-Wolf, 2009, Old mice retain bone marrow B1 progenitors, but lose B2 precursors, and exhibit altered immature B cell phenotype and light chain usage, Mech. Ageing Dev., 130, 401, 10.1016/j.mad.2009.04.001 Anolik, 2004, Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus, Arthritis Rheum., 40, 3580, 10.1002/art.20592 Appay, 2002, Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections, Nat. Med., 8, 379, 10.1038/nm0402-379 Appay, 2010, The role of the thymus in immunosenescence: lessons from the study of thymectomized individuals, Ageing, 2, 78 Balistreri, 2007, Role of TLR4 polymorphisms in inflammatory responses: implications for unsuccessful ageing, Ann. N. Y. Acad. Sci., 1119, 203, 10.1196/annals.1404.003 Balistreri, 2008, Role of polymorphisms of CC-chemokine receptor-5 gene in acute myocardial infarction and biological implications for longevity, Haematologica, 93, 637, 10.3324/haematol.12239 Banerjee, 2002, Age- and tissue-specific differences in human germinal center B cell selection revealed by analysis of IgVH gene hypermutation and lineages trees, Eur. J. Immunol., 32, 1947, 10.1002/1521-4141(200207)32:7<1947::AID-IMMU1947>3.0.CO;2-1 Black, 1978, Expression of IgD by murine lymphocytes: loss of surface IgD indicates maturation of memory B cells, J. Exp. Med., 147, 984, 10.1084/jem.147.4.984 Blink, 2005, Early appearance of germinal center-derived memory B cells and plasma cells in blood after primary immunization, J. Exp. Med., 201, 545, 10.1084/jem.20042060 Breitbart, 2002, Altered memory B-cell homeostasis in human ageing, J. Gerontol. A: Biol. Sci. Med. Sci., 57, B304, 10.1093/gerona/57.8.B304 Britschgi, 2007, Systemic and acquired immune responses in Alzheimer's disease, Int. Rev. Neurobiol., 82, 205, 10.1016/S0074-7742(07)82011-3 Bruunsgaard, 2003, Elevated levels of tumor necrosis factor alpha and mortality in centenarians, Am. J. Med., 115, 278, 10.1016/S0002-9343(03)00329-2 Bulati, 2008, Understanding ageing: biomedical and bioengineering approaches, the immunologic view, Immun. Ageing, 5, 9, 10.1186/1742-4933-5-9 Cancro, 2009, B cells and ageing: molecules and mechanisms, Trends Immunol., 30, 313, 10.1016/j.it.2009.04.005 Candore, 1997, Prevalence of organ-specific and non organ-specific autoantibodies in healthy centenarians, Mech. Ageing Dev., 94, 183, 10.1016/S0047-6374(96)01845-3 Candore, 2007, Genetic control of immune response in carriers of the 8.1 ancestral haplotype: correlation with levels of IgG subclasses: its relevance in the pathogenesis of autoimmune diseases, Ann. N. Y. Acad. Sci., 1110, 151, 10.1196/annals.1423.017 Candore, 2008, Immunosenescence and anti-immunosenescence therapies: the case of probiotics, Rejuven. Res., 11, 425, 10.1089/rej.2008.0662 Cevenini, 2010, Age-related inflammation: the contribution of different organs, tissues and systems. how to face it for therapeutic approaches, Curr. Pharm. Des., 16, 609, 10.2174/138161210790883840 Chong, 2003, Age-related accumulation of Ig V(H) gene somatic mutations in peripheral B cells from aged humans, Clin. Exp. Immunol., 133, 59, 10.1046/j.1365-2249.2003.02185.x Chong, 2005, CD27+ (memory) B cells decrease and apoptosis-resistant CD27− (naïve) B cells increase in aged humans: implication for age-related peripheral B cell developmental disturbances, Int. Immunol., 17, 383, 10.1093/intimm/dxh218 Colonna Romano, 2002, Age- and gender-related values of lymphocyte subsets in subjects from northern and southern Italy, Arch. Gerontol. Geriatr. (Suppl), 8, 99, 10.1016/S0167-4943(02)00109-7 Colonna Romano, 2003, B cells in the aged: CD27, CD5 and CD40 expression, Mech. Ageing Dev., 124, 389, 10.1016/S0047-6374(03)00013-7 Colonna Romano, 2009, A double-negative (IgD−CD27−) B cell population is increased in the peripheral blood of elderly people, Mech. Ageing Dev., 130, 81, 10.1016/j.mad.2009.08.003 Colonna Romano, 2010, B cell compartment in centenarian offspring and old people, Curr. Pharm. Des., 16, 604, 10.2174/138161210790883750 Cossarizza, 1996, CD45 isoforms expression on CD4+ and CD8+ T cells throughout life, from newborns to centenarians: implications for T cell memory, Mech. Ageing Dev., 86, 173, 10.1016/0047-6374(95)01691-0 Dalloul, 2009, CD5: a safeguard against autoimmunity and a shield for cancer cells, Autoimmun. Rev., 8, 349, 10.1016/j.autrev.2008.11.007 De Fanis, 2008, T-lymphocytes expressing CC chemokine receptor-5 are increased in frail older adults, J. Am. Geriatr. Soc., 56, 904, 10.1111/j.1532-5415.2008.01673.x Derhovanessian, 2010, Hallmark features of immunosenescence are absent in familial longevity, J. Immunol., 185, 4618, 10.4049/jimmunol.1001629 Di Bona, 2008, Association between the interleukin-1beta polymorphisms and Alzheimer's disease: a systematic review and meta-analysis, Brain Res. Rev., 59, 155, 10.1016/j.brainresrev.2008.07.003 Di Bona, 2009, Systematic review by meta-analyses on the possible role of TNF-alpha polymorphisms in association with Alzheimer's disease, Brain Res. Rev., 61, 60, 10.1016/j.brainresrev.2009.05.001 Dorner, 2005, Selecting B cells and plasma cells to memory, J. Exp. Med., 201, 497, 10.1084/jem.20050218 Duddy, 2004, Distinct profiles of human B cell effector cytokines, J. Immunol., 172, 3422, 10.4049/jimmunol.172.6.3422 Ershler, 2000, Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty, Ann. Rev. Med., 51, 245, 10.1146/annurev.med.51.1.245 Fagnoni, 1996, Expansion of cytotoxic CD8+CD28− T cells in healthy ageing people, including centenarians, Immunology, 88, 501, 10.1046/j.1365-2567.1996.d01-689.x Faria, 1998, Aging and immunoglobulin isotype patterns in oral tolerance, Braz. J. Med. Biol. Res., 31, 35, 10.1590/S0100-879X1998000100005 Faria, 2008, Variation rhythms of lymphocyte subsets during healthy ageing, Neuroimmunomodulation, 15, 365, 10.1159/000156478 Fecteau, 2003, CD40 stimulation of human peripheral B lymphocytes: distinct response from naïve and memory cells, J. Immunol., 171, 4621, 10.4049/jimmunol.171.9.4621 Fecteau, 2006, A new memory CD27−IgG+ B cell population in peripheral blood expressing VH genes with low frequency of somatic mutation, J. Immunol., 177, 3728, 10.4049/jimmunol.177.6.3728 Forconi, 2004, Hairy cell leukemia: at the crossroad of somatic mutation and isotype switch, Blood, 104, 3312, 10.1182/blood-2004-03-0950 Franceschi, 1995, The immunology of exceptional individuals: the lessons of centenarian, Immunol. Today, 16, 12, 10.1016/0167-5699(95)80064-6 Franceschi, 2000, Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space, Vaccine, 18, 1717, 10.1016/S0264-410X(99)00513-7 Franceschi, 2000, The network and the remodeling theories of ageing: historical background and new perspectives, Exp. Gerontol., 35, 879, 10.1016/S0531-5565(00)00172-8 Franceschi, 2000, Inflamm-ageing. An evolutionary perspective on immunosenescence, Ann. N. Y. Acad. Sci., 908, 244, 10.1111/j.1749-6632.2000.tb06651.x Franceschi, 2005, Genes involved in immune response/inflammation, IGF1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians, Mech. Ageing Dev., 126, 351, 10.1016/j.mad.2004.08.028 Franceschi, 2007, Inflammageing and anti-inflammageing: a systemic perspective of ageing and longevity emerged from studies in humans, Mech. Ageing Dev., 128, 92, 10.1016/j.mad.2006.11.016 Frasca, 2004, Reduced Ig class switch in aged mice correlates with decreased E47 and activation-induced cytidine deaminase, J. Immunol., 172, 2155, 10.4049/jimmunol.172.4.2155 Frasca, 2005, Humoral immune response and B-cell functions including immunoglobulin class switch are downregulated in aged mice and humans, Sem. Immunol., 17, 378, 10.1016/j.smim.2005.05.005 Frasca, 2007, Aging murine B cells have decreased class switch induced by anti-CD40 or BAFF, Exp. Gerontol., 42, 192, 10.1016/j.exger.2006.09.003 Frasca, 2008, Ageing down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells, J. Immunol., 180, 5283, 10.4049/jimmunol.180.8.5283 Frasca, 2010, Intrinsic defects in B cell response to seasonal influenza vaccination in elderly humans, Vaccine, 10.1016/j.vaccine.2010.10.023 Frasca, 2010, Age effects on B cells and humoral immunity in humans, Ageing Res Rev Gao, 2008, Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression, Trends Immunol., 29, 357, 10.1016/j.it.2008.05.002 Gardner, 2006, Age-related changes in the immune response to influenza vaccination in a racially diverse, healthy elderly population, Vaccine, 24, 1609, 10.1016/j.vaccine.2005.09.058 Genton, 2006, Hepatitis A vaccines and the elderly, Travel. Med. Infect. Dis., 4, 303, 10.1016/j.tmaid.2005.10.002 Gibson, 2009, B-cell diversity decreases in old age and is correlated with poor health status, Ageing Cell, 8, 18, 10.1111/j.1474-9726.2008.00443.x Ginaldi, 2001, Immunosenescence and infectious diseases, Microb. Infect., 3, 851, 10.1016/S1286-4579(01)01443-5 Ginaldi, 2005, Osteoporosis, inflammation and ageing, Immun. Ageing, 2, 14, 10.1186/1742-4933-2-14 Globerson, 2000, Ageing of lymphocytes and lymphocytes in the aged, Immunol. Today, 21, 515, 10.1016/S0167-5699(00)01714-X Gruver, 2007, Immunosenescence of ageing, J. Pathol., 211, 144, 10.1002/path.2104 Guerrettaz, 2008, Acquired hematopoietic stem cell defects determine B-cell repertoire changes associated with aging, Proc. Natl. Acad. Sci. U.S.A., 105, 11898, 10.1073/pnas.0805498105 Gupta, 2005, Life and death of lymphocytes: a role in immunesenescence, Immun. Ageing, 2, 12, 10.1186/1742-4933-2-12 Harris, 2000, Reciprocal regulation of polarized cytokine production by effector B and T cell, Nat. Immunol., 1, 475, 10.1038/82717 Huppert, 1998, Ageing and lymphocyte subpopulations: whole-blood analysis of immune markers in a large population sample of healthy elderly individuals, Exp. Gerontol., 33, 593, 10.1016/S0531-5565(98)00033-3 Inamine, 2005, Two waves of memory B cell generation in the primary immune response, Int. Immunol., 17, 581, 10.1093/intimm/dxh241 Johnson, 2002, Aging and developmental transitions in the B cell lineage, Int. Immunol., 14, 1313, 10.1093/intimm/dxf092 Kline, 1999, B cell maintenance in aged mice reflects both increased B cell longevity and decreased B cell generation, J. Immunol., 162, 3342, 10.4049/jimmunol.162.6.3342 Klein, 1998, Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells, J. Exp. Med., 188, 1679, 10.1084/jem.188.9.1679 Koga, 2000, Evidence for early aging in the mucosal immune system, J. Immunol., 165, 5352, 10.4049/jimmunol.165.9.5352 Kolar, 2006, Diversity of the Ig repertoire is maintained with age in spite of reduced germinal centre cells in human tonsil lymphoid tissue, Scand. J. Immunol., 64, 314, 10.1111/j.1365-3083.2006.01817.x Kolibab, 2005, Immune response to pneumococcal polysaccharides 4 and 14 in elderly and young adults: analysis of the variable heavy chain repertoire, Infect. Immun., 73, 7465, 10.1128/IAI.73.11.7465-7476.2005 Kriangkum, 2004, Clonotypic IgH VDJ sequence analysis in Waldenstrom's macroglobulinemia suggests an unusual B cell origin and expansion of polyclonal B cells in peripheral blood, Blood, 104, 2134, 10.1182/blood-2003-11-4024 Kruetzmann, 2003, Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen, J. Exp. Med., 197, 939, 10.1084/jem.20022020 LeMaoult, 1997, Clonal expansions of B lymphocytes in old mice, J. Immunol., 159, 3866, 10.4049/jimmunol.159.8.3866 Libby, 2002, Inflammation in atherosclerosis, Nature, 420, 868, 10.1038/nature01323 Linton, 2004, Age-related changes in lymphocyte development and function, Nat. Immunol., 5, 133, 10.1038/ni1033 Lio, 2004, Opposite effects of interleukin 10 common gene polymorphisms in cardiovascular diseases and in successful ageing: genetic background of male centenarians is protective against coronary heart disease, J. Med. Genet., 41, 790, 10.1136/jmg.2004.019885 Listì, 2006, A study of serum immunoglobulin levels in elderly persons that provides new insights into B cell immunosenescence, Ann. N. Y. Acad. Sci., 1089, 487, 10.1196/annals.1386.013 Lougaris, 2005, Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features, Immunol. Rev., 203, 48, 10.1111/j.0105-2896.2005.00229.x Manz, 1997, Lifetime of plasma cells in the bone marrow, Nature, 388, 133, 10.1038/40540 Martin, 2006, B cell immunobiology in disease: evolving concepts from the clinic, Annu. Rev. Immunol., 24, 467, 10.1146/annurev.immunol.24.021605.090517 McElhaney, 2009, Immunosenescence: what does it mean to health outcomes in older adults?, Curr. Opin. Immunol., 21, 418, 10.1016/j.coi.2009.05.023 McKenna, 2001, Immunophenotypic analysis of hematogones (B-lymphocyte precursors) in 662 consecutive bone marrow specimens by 4-color flow cytometry, Blood, 98, 2498, 10.1182/blood.V98.8.2498 Miller, 2003, The decline in B lymphopoiesis in aged mice reflects loss of very early B-lineage precursors, J. Immunol., 171, 2326, 10.4049/jimmunol.171.5.2326 Miller, 2007, B cell and ageing: balancing the homeostatic equation, Exp. Gerontol., 42, 396, 10.1016/j.exger.2007.01.010 Minges Wols, 2009, Migration of immature and mature B cells in the aged microenvironment, Immunology, 129, 278, 10.1111/j.1365-2567.2009.03182.x Monsonego, 2003, Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimers disease, J. Clin. Invest., 112, 415, 10.1172/JCI200318104 Murasko, 2002, Role of humoral and cell-mediated immunity in protection from influenza disease after immunization of healthy elderly, Exp. Gerontol., 37, 427, 10.1016/S0531-5565(01)00210-8 Nakiri, 2007, Expression of CD22 on peripheral B cells in patients with rheumatoid arthritis: relation to CD5-positive B cells, Clin. Rheumatol., 26, 1721, 10.1007/s10067-007-0665-3 Nicholson, 1997, Acute viral infections of upper respiratory tract in elderly people living in the community: comparative, prospective, population based study of disease burden, BMJ, 315, 1060, 10.1136/bmj.315.7115.1060 Nicoletti, 1991, Repertoire diversity of antibody response to bacterial antigens in aged mice, II. Phosphorylcholine-antibody in young and aged mice differ in both VH/VL gene repertoire and in specificity, J. Immunol., 147, 2750, 10.4049/jimmunol.147.8.2750 Nicoletti, 1993, Repertoire diversity of antibody response to bacterial antigens in aged mice, III. Phosphorylcholine antibody from young and aged mice differ in structure and protective activity against infection with Streptococcus pneumoniae, J. Immunol., 150, 543, 10.4049/jimmunol.150.2.543 Obukhanych, 2006, T-independent type II immune responses generate memory B cells, J. Exp. Med., 203, 305, 10.1084/jem.20052036 O’Mahony, 1998, Quantitative intracellular cytokine measurement: age-related changes in proinflammatory cytokine production, Clin. Exp. Immunol., 113, 213, 10.1046/j.1365-2249.1998.00641.x Ouyang, 2003, Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1), Exp. Gerontol., 38, 911, 10.1016/S0531-5565(03)00134-7 Paganelli, 1992, Changes in circulating B cells and immunoglobulin classes and subclasses in a healthy aged population, Clin. Exp. Immunol., 90, 351, 10.1111/j.1365-2249.1992.tb07954.x Pasare, 2005, Control of B-cell responses by Toll-like receptors, Nature, 438, 364, 10.1038/nature04267 Pawelec, 2002, T cells and ageing, Front. Biosci., 7, d1056, 10.2741/A831 Pawelec, 2004, Is immunosenescence infectious?, Trends Immunol., 25, 406, 10.1016/j.it.2004.05.006 Pawelec, 2005, Human immunosenescence: is it infectious?, Immunol. Rev., 20, 257, 10.1111/j.0105-2896.2005.00271.x Pawelec, 2008, Immunity and ageing in man: Annual Review 2006/2007, Exp. Gerontol., 43, 34 Pellicanò, 2010, Systemic immune response in Alzheimer's disease: in vitro mononuclear cell activation and cytokine production, J. Alzheimers Dis., 21, 181, 10.3233/JAD-2010-091714 Pes, 2004, Association between longevity and cytokine gene polymorphisms. A study in Sardinian centenarians, Aging Clin. Exp. Res., 16, 244, 10.1007/BF03327391 Pillai, 2004, Positive selection and lineage commitment during peripheral B lymphocyte development, Immunol. Rev., 197, 206, 10.1111/j.0105-2896.2003.097.x Pillai, 2005, Marginal zone B cells, Annu. Rev. Immunol., 23, 161, 10.1146/annurev.immunol.23.021704.115728 Pistoia, 1997, Production of cytokines by human B cells in health and disease, Immunol. Today, 18, 343, 10.1016/S0167-5699(97)01080-3 Qi, 2006, Extrafollicular activation of lymph node B cells by antigen-bearing dendritic cells, Science, 312, 1672, 10.1126/science.1125703 Riley, 1991, B cell precursors are decreased in senescent BALB/c mice, but retain normal mitotic activity in vivo and in vitro, Clin. Immunol. Immunopathol., 59, 301, 10.1016/0090-1229(91)90026-7 Rogers, 1998, Expression of immune system associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease, Neurobiol. Ageing, 9, 339, 10.1016/S0197-4580(88)80079-4 Rossi, 2003, B lymphopoiesis is active throughout human life, but there are developmental age-related changes, Blood, 101, 576, 10.1182/blood-2002-03-0896 Sansoni, 1993, Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians, Blood, 82, 2767, 10.1182/blood.V82.9.2767.2767 Sanz, 2007, B cell depletion therapy in autoimmune disease, Front. Biosci., 12, 2546, 10.2741/2254 Sanz, 2008, Phenotypic and functional heterogeneity of human memory B cells, Semin. Immunol., 20, 67, 10.1016/j.smim.2007.12.006 Schenkein, 2008, Pneumococcal vaccination in older adults induces antibodies with low opsonic capacity and reduced antibody potency, Vaccine, 26, 5521, 10.1016/j.vaccine.2008.07.071 Schultze, 1999, Human non-germinal center B cell interleukin (IL)-12 production is primarily regulated by T cell signals CD40 ligand, interferon gamma, and IL-10: role of B cells in the maintenance of T cell responses, J. Exp. Med., 189, 1, 10.1084/jem.189.1.1 Semba, 2005, T cell subsets and mortality in older community-dwelling women, Exp. Gerontol., 40, 81, 10.1016/j.exger.2004.09.006 Shi, 2005, Regulation of aged humoral immune defense against pneumococcal bacteria by IgM memory B cell, J. Immunol., 175, 3262, 10.4049/jimmunol.175.5.3262 Shriner, 2006, Analysis of the young and elderly variable gene repertoire in response to pneumococcal polysaccharides using a reconstituted SCID mouse model, Vaccine, 24, 7159, 10.1016/j.vaccine.2006.06.055 Smithson, 2005, Immune response to pneumococcal polysaccharides 4 and 14 in elderly and young adults: analysis of the variable light chain repertoire, Infect. Immun., 73, 7477, 10.1128/IAI.73.11.7477-7484.2005 Speciale, 2007, Lymphocyte subset patterns and cytokine production in Alzheimer's disease patients, Neurobiol. Ageing, 28, 1163, 10.1016/j.neurobiolaging.2006.05.020 Spencer, 1998, Human marginal-zone B cells, Immunol. Today, 19, 421, 10.1016/S0167-5699(98)01308-5 Speziali, 2009, Specific immune responses but not basal functions of B and T cells are impaired in aged mice, Cell. Immunol., 256, 1, 10.1016/j.cellimm.2009.01.010 Tangye, 2004, Divide and conquer: the importance of cell division in regulating B cell responses, Immunology, 112, 509, 10.1111/j.1365-2567.2004.01950.x Terry, 2004, Cardiovascular disease delay in centenarian offspring, J. Gerontol. A: Biol. Sci. Med. Sci., 59, 385, 10.1093/gerona/59.4.M385 Terry, 2004, Cardiovascular advantages among the offspring of centenarians, J. Am. Geriatr. Soc., 52, 2074, 10.1111/j.1532-5415.2004.52561.x Toellner, 2002, Low-level hypermutation in T cell-independent germinal centers compared with high mutation rates associated with T cell-dependent germinal centers, J. Exp. Med., 195, 383, 10.1084/jem.20011112 van Baarle, 2005, Significance of senescence for virus-specific memory T cell responses: rapid ageing during chronic stimulation of the immune system, Immunol. Lett., 97, 19, 10.1016/j.imlet.2004.10.003 Vasto, 2004, Immunity & Ageing: a new journal looking at ageing from an immunological point of view, Immun. Ageing, 29, 1, 10.1186/1742-4933-1-1 Vasto, 2007, Role of persistent CMV infection in configuring T cell immunity in the elderly, Immun. Ageing, 4, 2, 10.1186/1742-4933-4-2 Veneri, 2009, Expression of CD27 and CD23 on peripheral blood B lymphocytes in humans of different ages, Blood Transfus., 7, 29 Wack, 1998, Age-related modifications of the human alphabeta T cell repertoire due to different clonal expansions in the CD4+ and CD8+ subsets, Int. Immunol., 10, 1281, 10.1093/intimm/10.9.1281 Wang, 1999, Immunoglobulin VH gene expression in human aging, Clin. Immunol., 93, 132, 10.1006/clim.1999.4781 Wei, 2007, A new population of cells lacking expression of CD27 represents a notable component of the B cell memory compartment in systemic lupus erythematosus, J. Immunol., 178, 6624, 10.4049/jimmunol.178.10.6624 Weinberger, 2008, Biology of immune responses to vaccine in elderly persons, Clin. Infect. Dis., 46, 1078, 10.1086/529197 Weinberger, 2009, Immunology and ageing, 23 Weksler, 2000, The effect of age on the B-cell repertoire, J. Clin. Immunol., 20, 240, 10.1023/A:1006659401385 Weksler, 2000, Changes in the B-cell repertoire with age, Vaccine, 18, 1624, 10.1016/S0264-410X(99)00497-1 Weksler, 2002, Patients with Alzheimer disease have lower levels of serum anti-amyloid peptide antibodies than healthy elderly individuals, Exp. Gerontol., 37, 943, 10.1016/S0531-5565(02)00029-3 Weller, 2001, CD40-CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans, Proc. Natl. Acad. Sci. U.S.A., 98, 1166, 10.1073/pnas.98.3.1166 Weller, 2004, Human blood IgM “memory” B cells are circulating splenic marginal zone B cells Harboring a prediversified immunoglobulin repertoire, Blood, 104, 3647, 10.1182/blood-2004-01-0346 Weller, 2005, Splenic marginal zone B cells in humans: where do they mutate their Ig receptor?, Eur. J. Immunol., 35, 2789, 10.1002/eji.200535446 Weng, 2009, CD28-T cells: their role in the age-associated decline of the immune function, Trends Immunol., 30, 306, 10.1016/j.it.2009.03.013 Wikby, 1994, Age related changes in immune parameters in a very old population of Swedish people: a longitudinal study, Exp. Gerontol., 29, 531, 10.1016/0531-5565(94)90036-1 William, 2002, Evolution of autoantibody responses via somatic hypermutation outside of germinal centers, Science, 297, 2066, 10.1126/science.1073924 Wolniak, 2004, The germinal center response, Crit. Rev. Immunol., 24, 39, 10.1615/CritRevImmunol.v24.i1.20 Wu, 2010, High throughput immunoglobulin repertoire analysis distinguishes between human IgM memory and switched memory B cell populations, Blood, 116, 1070, 10.1182/blood-2010-03-275859 Xiao, 2004, CD27 is acquired by primed B cells at the centroblast stage and promotes germinal center formation, J. Immunol., 172, 7432, 10.4049/jimmunol.172.12.7432 Yan, 2010, The effect of ageing on human lymphocyte subsets: comparison of males and females, Immun. Ageing, 7, 4, 10.1186/1742-4933-7-4 Youinou, 1988, The importance of CD5-positive B cells in nonorgan-specific autoimmune diseases, Scand. J. Rheumatol., 76, 243, 10.3109/03009748809102975 Zheng, 1997, Immunosenescence and germinal center reaction, Immunol. Rev., 160, 63, 10.1111/j.1600-065X.1997.tb01028.x Zhong, 2009, A novel subpopulation of B-1 cells is enriched with autoreactivity in normal and lupus-prone mice, Arthritis Rheum., 60, 3734, 10.1002/art.25015