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International Consensus Document (ICON): Common Variable Immunodeficiency Disorders
2015; Elsevier BV; Volume: 4; Issue: 1 Linguagem: Inglês
10.1016/j.jaip.2015.07.025
ISSN2213-2201
AutoresFrancisco A. Bonilla, Işıl Barlan, Helen Chapel, Beatriz Tavares Costa‐Carvalho, Charlotte Cunningham‐Rundles, M. Teresa de la Morena, Francisco Espinosa‐Rosales, Lennart Hammarström, Shigeaki Nonoyama, Isabella Quinti, John M. Routes, Mimi L.K. Tang, Klaus Warnatz,
Tópico(s)Blood disorders and treatments
ResumoThe International Collaboration in Asthma, Allergy and Immunology initiated an international coalition among the American Academy of Allergy, Asthma & Immunology; the European Academy of Allergy and Clinical Immunology; the World Allergy Organization; and the American College of Allergy, Asthma & Immunology on common variable immunodeficiency. An author group was formed and then divided into individual committees. Within the committee, teams of authors were subgrouped to generate content for specific sections of the document. Content was derived from literature searches, relevant published guidelines, and clinical experience. After a draft of the document was assembled, it was collectively reviewed and revised by the authors. Where evidence was lacking or conflicting, the information presented represents the consensus expert opinion of the group. The full document was then independently reviewed by 5 international experts in the field, none of whom was among the authors of the original. The comments of these reviewers were incorporated before submission for publication. The term “common variable immunodeficiency” (CVID) was coined in 1971 by a World Health Organization committee to separate less well-defined antibody deficiency syndromes from others with a more coherent clinical description and Mendelian inheritance.1Fudenberg H. Good R.A. Goodman H.C. Hitzig W. Kunkel H.G. Roitt I.M. et al.Primary immunodeficiencies: report of a World Health Organization Committee.Pediatrics. 1971; 47: 927-946PubMed Google Scholar, 2Cooper M.D. Faulk W.P. Fudenberg H.H. Good R.A. Hitzig W. Kunkel H. et al.Classification of primary immunodeficiencies.N Engl J Med. 1973; 288: 966-967Crossref PubMed Google Scholar Therefore, the hypogammaglobulinemic syndrome of CVID became a diagnosis of exclusion. Since then, the International Union of Immunological Societies Expert Primary Immunodeficiency Committee redefined the conditions in 2009 as “common variable immunodeficiency disorders”, thus retaining the CVID acronym but emphasizing the heterogeneous nature of these hypogammaglobulinemic states.3Notarangelo L.D. Fischer A. Geha R.S. Casanova J.L. Chapel H. Conley M.E. et al.Primary immunodeficiencies: 2009 update.J Allergy Clin Immunol. 2009; 124: 1161-1178Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar According to the proposal by the European Society for Immunodeficiencies and the Pan American Group for Immunodeficiency in 1999, CVID was defined as follows:CVID is probable in a male or female patient who has a marked decrease of IgG (at least 2 SD below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA, and fulfills all of the following criteria:1. Onset of immunodeficiency at greater than 2 years of age2. Absent isohemagglutinins and/or poor response to vaccines3. Defined causes of hypogammaglobulinemia have been excluded according to a list of differential diagnosis (Table I).As will be discussed further below, CVID encompasses a group of heterogeneous primary antibody failure syndromes characterized by hypogammaglobulinemia. The number of potential distinct entities within this group is still unknown, and the diagnosis remains one of exclusion. Monogenic forms have been described, but polygenic inheritance is likely in most cases.4Orange J.S. Glessner J.T. Resnick E. Sullivan K.E. Lucas M. Ferry B. et al.Genome-wide association identifies diverse causes of common variable immunodeficiency.J Allergy Clin Immunol. 2011; 127: 1360-1367.e6Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 5Yong P.F. Thaventhiran J.E. Grimbacher B. “A rose is a rose is a rose,” but CVID is not CVID common variable immune deficiency (CVID), what do we know in 2011?.Adv Immunol. 2011; 111: 47-107Crossref PubMed Scopus (61) Google Scholar, 6Keller M.D. Jyonouchi S. Chipping away at a mountain: genomic studies in common variable immunodeficiency.Autoimmun Rev. 2013; 12: 687-689Crossref PubMed Scopus (8) Google Scholar Despite the fact that several monogenic defects underlying apparent CVID have been defined, because of the rarity of each defect and the lack in most cases of significant impact on management, as well as the cost of testing, genetic studies are not considered appropriate for routine use in patients with CVID at this time.Table IDifferential diagnosis of hypogammaglobulinemiaDrug induced Antimalarial agents Captopril Carbamazepine Glucocorticoids Fenclofenac Gold salts Penicillamine Phenytoin Sulfasalazine Anti-CD20 mAbs (rituximab)Single gene and other defects Ataxia telangiectasia Autosomal-recessive forms of SCID and other forms of combined immunodeficiency Hyper-IgM syndromes Transcobalamin II deficiency and hypogammaglobulinemia X-linked agammaglobulinemia X-linked lymphoproliferative disorder (EBV-associated) X-linked SCID Some metabolic disordersChromosomal anomalies Chromosome 18q- syndrome Monosomy 22 Trisomy 8 Trisomy 21Infectious diseases HIV Congenital infection with rubella virus Congenital infection with cytomegalovirus Congenital infection with Toxoplasma gondii EBVMalignancy Chronic lymphocytic leukemia Immunodeficiency with thymoma Non-Hodgkin lymphoma Monoclonal gammopathy (mutiple myeloma, Waldenstrom macroglobulinemia)Other systemic disorders Immunodeficiency caused by excessive loss of immunoglobulins (nephrosis, severe burns, lymphangiectasia, protein-losing enteropathy)SCID, Severe combined immunodeficiency. Open table in a new tab SCID, Severe combined immunodeficiency. The onset of the varied clinical manifestations and laboratory abnormalities do not necessarily coincide, and may occur at any age from early childhood to old age. Given (1) the broad differential diagnosis of hypogammaglobulinemia (Table I),7Kutukculer N. Karaca N.E. Demircioglu O. Aksu G. Increases in serum immunoglobulins to age-related normal levels in children with IgA and/or IgG subclass deficiency.Pediatr Allergy Immunol. 2007; 18: 167-173Crossref PubMed Scopus (26) Google Scholar (2) the challenge of differentiating some of these in early childhood (particularly regarding definitive assessment of vaccine responses), and (3) that CVID is considered a diagnosis of exclusion, it is best not to confer this diagnosis before at least age 4 years. Antibody production is always disturbed in CVID. This is often the result of B-cell dysfunction, but may also result primarily from impairment of T-cell function and lack of sufficient help for antibody production. Infection susceptibility is mainly to encapsulated extracellular bacteria in the respiratory tract, but there may also occur various other clinical manifestations affecting many organ systems. The phenotype is very broad, ranging from only bacterial infections, to progression from a CVID-like condition to severe disease similar to a combined immunodeficiency, possibly having a different etiology.8Chapel H. Lucas M. Patel S. Lee M. Cunningham-Rundles C. Resnick E. et al.Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts.J Allergy Clin Immunol. 2012; 130: 1197-1198.e9Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 9Malphettes M. Gerard L. Carmagnat M. Mouillot G. Vince N. Boutboul D. et al.Late-onset combined immune deficiency: a subset of common variable immunodeficiency with severe T cell defect.Clin Infect Dis. 2009; 49: 1329-1338Crossref PubMed Scopus (64) Google Scholar Some patients may also have distinct initial presentations, such as autoimmune disease, granulomatous disease, or enteropathy without recurrent infections (discussed in detail below).10Agarwal S. Cunningham-Rundles C. Autoimmunity in common variable immunodeficiency.Curr Allergy Asthma Rep. 2009; 9: 347-352Crossref PubMed Scopus (67) Google Scholar, 11Quinti I. Soresina A. Spadaro G. Martino S. Donnanno S. Agostini C. et al.Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency.J Clin Immunol. 2007; 27: 308-316Crossref PubMed Scopus (203) Google Scholar The normal range of IgG serum levels varies in different age groups; therefore, it is critical that this be defined according to the age-adjusted reference range for the population. An absolute lower limit value of IgG at 4.5 g/L for adults has been proposed, because nearly 95% of the patients with CVID in a European cohort fulfilled this criterion.12Chapel H. Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions.Br J Haematol. 2009; 145: 709-727Crossref PubMed Scopus (128) Google Scholar However, it is recognized that some patients with CVID have relatively high residual IgG levels (up to 6 g/L) at diagnosis while still showing impaired specific antibody formation.13Cunningham-Rundles C. How I treat common variable immune deficiency.Blood. 2010; 116: 7-15Crossref PubMed Scopus (102) Google Scholar Furthermore, the normal range of IgG levels may also vary according to race or ethnicity.14Kardar G. Oraei M. Shahsavani M. Namdar Z. Kazemisefat G. Haghi Ashtiani M. et al.Reference intervals for serum immunoglobulins IgG, IgA, IgM and complements C3 and C4 in Iranian healthy children.Iran J Public Health. 2012; 41: 59-63PubMed Google Scholar Thus, for practical purposes, the definition of hypogammaglobulinemia depends on the local or regional reference range applicable to the patient. In addition to a low IgG level, IgA or IgM level must be low for a definite diagnosis of CVID.15Ozen A. Baris S. Karakoc-Aydiner E. Ozdemir C. Bahceciler N.N. Barlan I.B. Outcome of hypogammaglobulinemia in children: immunoglobulin levels as predictors.Clin Immunol. 2010; 137: 374-383Crossref PubMed Scopus (11) Google Scholar Note that not all clinical immunologists agree regarding these laboratory criteria. Some do not confer a diagnosis of CVID if the IgA level is normal. We publish the less stringent criteria here because it is an accepted standard for many practitioners. It is of critical importance that all immunoglobulin measurements be interpreted according to age-specific normal ranges and that levels be consistently low on repeated measurements at least 3 weeks apart. Vaccine responses will be discussed later in greater depth. Impairment of IgG vaccine responses is an extremely important element of the definition of CVID. Note that depending on circumstances, some immunologists forego antibody measurement, for example, if the total IgG level is very low (<100 mg/dL) or if the clinical presentation and other laboratory features are highly characteristic; see section on Diagnosis). 1.Most patients will have at least 1 of the characteristic clinical manifestations (infection, autoimmunity, lymphoproliferation). However, a diagnosis of CVID may be conferred on asymptomatic individuals who fulfill criteria 2 to 5, especially in familial cases.2.Hypogammaglobulinemia should be defined according to the age-adjusted reference range for the laboratory in which the measurement is performed. The IgG level must be repeatedly low in at least 2 measurements more than 3 weeks apart in all patients. Repeated measurement may be omitted if the level is very low (<100-300 mg/dL depending on age), other characteristic features are present, and it is considered in the best interest of the patient to initiate therapy with IgG as quickly as possible.3.IgA or IgM level must also be low. (Note that some experts prefer a more narrow definition requiring low IgA level in all patients.)4.It is strongly recommended that all patients with an IgG level of more than 100 mg/dL should be studied for responses to T-dependent (TD) and T-independent (TI) antigens, whenever possible. In all patients undergoing such testing, there must be a demonstrable impairment of response to at least 1 type of antigen (TD or TI). At the discretion of the practitioner, specific antibody measurement may be dispensed with if all other criteria are satisfied and if the delay incurred by prevaccination and postvaccination antibody measurement is thought to be deleterious to the patient's health.5.Other causes of hypogammaglobulinemia must be excluded (Table I).6.Genetic studies to investigate monogenic forms of CVID or for disease-modifying polymorphisms are not generally required for diagnosis and management in most of the patients, especially those who present with infections only without immune dysregulation, autoimmunity, malignancy, or other complications. In these latter groups of patients, however, single gene defects may be amenable to specific therapies (eg, stem cell therapy) and molecular genetic diagnosis should be considered when possible. Ameratunga et al16Ameratunga R. Woon S.T. Gillis D. Koopmans W. Steele R. New diagnostic criteria for CVID.Expert Rev Clin Immunol. 2014; 10: 183-186Crossref PubMed Scopus (1) Google Scholar have recently proposed a distinct set of diagnostic criteria for CVID. Differences between the criteria of Ameratunga et al16Ameratunga R. Woon S.T. Gillis D. Koopmans W. Steele R. New diagnostic criteria for CVID.Expert Rev Clin Immunol. 2014; 10: 183-186Crossref PubMed Scopus (1) Google Scholar and those stated above are summarized in Table II. Although the criteria presented here do not define “possible” or “probable” forms of CVID, we recognize that some patients with a low IgG level and impaired vaccine responses may not fulfill our criteria for CVID (at least at initial evaluation) because IgA or IgM level is not low. This is a form of hypogammaglobulinemia with antibody deficiency that should not be called CVID (it may be called “unspecified IgG deficiency” or “unspecified hypogammaglobulinemia”). Alternatively, IgG and IgA levels may be low, but vaccine responses may appear normal by standard criteria. In all these cases, patients should be assessed repeatedly over time because immunoglobulin levels and antibody function may wane to the point that the above criteria are met and a diagnosis of CVID may be conferred. Regardless of whether there is deterioration over time, many patients with abnormal immunoglobulin levels and/or functional antibody responses not meeting criteria for CVID may have a significant burden of infections and should be assessed for benefit from IgG replacement.Table IIDifferences between the definition of CVID ICON vs Ameratunga et al16Ameratunga R. Woon S.T. Gillis D. Koopmans W. Steele R. New diagnostic criteria for CVID.Expert Rev Clin Immunol. 2014; 10: 183-186Crossref PubMed Scopus (1) Google ScholarCVID ICONAmeratunga et al16Ameratunga R. Woon S.T. Gillis D. Koopmans W. Steele R. New diagnostic criteria for CVID.Expert Rev Clin Immunol. 2014; 10: 183-186Crossref PubMed Scopus (1) Google ScholarThe diagnosis is “definite” if all criteria are met.The diagnosis is “probable” if all criteria are met.“Probable” or “possible” CVID is not defined.Both “probable” and “possible” CVID are defined; there is no “definite” CVID.Serum IgG level must be below local/regional clinical laboratory norms.Serum IgG must be 50%), and in most of them, CVID is the most frequent symptomatic antibody deficiency diagnosed in adulthood.20Leiva L.E. Zelazco M. Oleastro M. Carneiro-Sampaio M. Condino-Neto A. Costa-Carvalho B.T. et al.Primary immunodeficiency diseases in Latin America: the second report of the LAGID registry.J Clin Immunol. 2007; 27: 101-108Crossref PubMed Scopus (71) Google Scholar, 22Boyle J.M. Buckley R.H. Population prevalence of diagnosed primary immunodeficiency diseases in the United States.J Clin Immunol. 2007; 27: 497-502Crossref PubMed Scopus (142) Google Scholar IgA deficiency occurs with higher frequency overall, but most patients with IgA deficiency are asymptomatic.23Rachid R. Bonilla F.A. The role of anti-IgA antibodies in causing adverse reactions to gamma globulin infusion in immunodeficient patients: a comprehensive review of the literature.J Allergy Clin Immunol. 2012; 129: 628-634Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Note that in children, specific antibody deficiency is more often diagnosed.24Javier III, F.C. Moore C.M. Sorensen R.U. Distribution of primary immunodeficiency diseases diagnosed in a pediatric tertiary hospital.Ann Allergy Asthma Immunol. 2000; 84: 25-30Abstract Full Text PDF PubMed Google Scholar In 2007, a Latin American Group for Immunodeficiency registry report revealed that in a total of 3321 patients registered, the most common form of primary immunodeficiency disease was predominantly antibody deficiency (53.2%), with IgA deficiency and CVID reported as the most frequent types.20Leiva L.E. Zelazco M. Oleastro M. Carneiro-Sampaio M. Condino-Neto A. Costa-Carvalho B.T. et al.Primary immunodeficiency diseases in Latin America: the second report of the LAGID registry.J Clin Immunol. 2007; 27: 101-108Crossref PubMed Scopus (71) Google Scholar A recent report from the European Society for Immunodeficiencies registry database including 13,708 patients from 41 countries established that CVID represents the most common entity with 2880 patients or 21% of all entries.18Gathmann B. Binder N. Ehl S. Pourpak Z. Rezaei N. Abolmaali K. The European internet-based patient and research database for primary immunodeficiencies: update 2011.Clin Exp Immunol. 2012; 167: 479-491Crossref PubMed Scopus (37) Google Scholar, 25Immunodeficiencies ESf. New ESID Registry 2013. Available from: http://esid.org/Working-Parties/Registry/New-ESID-Registry. Accessed November 15, 2014.Google Scholar The United States Immunodeficiency Network registry contains 3459 subjects, with 1049 subjects with CVID (30%).26Network USI. USIDNET Registry. Towson, MD: Immune Deficiency Foundation; 2014. Available from: http://www.usidnet.org/pub/Registries-Info. Accessed September 22, 2014.Google Scholar There are no precise data on the prevalence of CVID, but it has been estimated at between 1:100,000 and 1:10,000 of the population.12Chapel H. Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions.Br J Haematol. 2009; 145: 709-727Crossref PubMed Scopus (128) Google Scholar The European Society for Immunodeficiencies registry estimates a total primary immunodeficiency diseases (PIDD) prevalence ranging from 1.3 (Poland) to 5 (France) per 100,000 living persons in European countries.18Gathmann B. Binder N. Ehl S. Pourpak Z. Rezaei N. Abolmaali K. The European internet-based patient and research database for primary immunodeficiencies: update 2011.Clin Exp Immunol. 2012; 167: 479-491Crossref PubMed Scopus (37) Google Scholar, 25Immunodeficiencies ESf. New ESID Registry 2013. Available from: http://esid.org/Working-Parties/Registry/New-ESID-Registry. Accessed November 15, 2014.Google Scholar The calculated prevalence of CVID in these European countries ranges from 0.07 to 0.98 patients per 100,000 inhabitants. These observed differences between countries are thought to be a consequence of underreporting in those showing the lower rates of prevalence.18Gathmann B. Binder N. Ehl S. Pourpak Z. Rezaei N. Abolmaali K. The European internet-based patient and research database for primary immunodeficiencies: update 2011.Clin Exp Immunol. 2012; 167: 479-491Crossref PubMed Scopus (37) Google Scholar The reported prevalence in Japan is also within this range (0.25:100,000).27Ishimura M. Takada H. Doi T. Imai K. Sasahara Y. Kanegane H. et al.Nationwide survey of patients with primary immunodeficiency diseases in Japan.J Clin Immunol. 2011; 31: 968-976Crossref PubMed Scopus (19) Google Scholar Discrepancies between these reports are likely a result of different methodologies and their influences on various forms of ascertainment bias. Additional factors in apparent geographic variance in incidence/prevalence could be due to access to health care, rate at which patients are properly diagnosed, or population genetic differences. With the exception of some known monogenic forms of CVID (discussed below), no cause for the immune defect has been found in 98% of the patients with CVID. With the hallmark of hypogammaglobulinemia, the immune defect common to all patients with CVID is loss of B-cell function. This is either intrinsic to B cells, or a result of insufficient help from other cells for antibody production. In particular, there is a reduction in the number and percentage of isotype-switched B cells in a majority (not all)28Warnatz K. Denz A. Drager R. Braun M. Groth C. Wolff-Vorbeck G. et al.Severe deficiency of switched memory B cells (CD27(+)IgM(−)IgD(−)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease.Blood. 2002; 99: 1544-1551Crossref PubMed Scopus (319) Google Scholar, 29Wehr C. Kivioja T. Schmitt C. Ferry B. Witte T. Eren E. et al.The EUROclass trial: defining subgroups in common variable immunodeficiency.Blood. 2008; 111: 77-85Crossref PubMed Scopus (277) Google Scholar and a loss of plasma cells in both bone marrow and mucosal tissues.30Ochtrop M.L. Goldacker S. May A.M. Rizzi M. Draeger R. Hauschke D. et al.T and B lymphocyte abnormalities in bone marrow biopsies of common variable immunodeficiency.Blood. 2011; 118: 309-318Crossref PubMed Scopus (27) Google Scholar, 31Taubenheim N. von Hornung M. Durandy A. Warnatz K. Corcoran L. Peter H.H. et al.Defined blocks in terminal plasma cell differentiation of common variable immunodeficiency patients.J Immunol. 2005; 175: 5498-5503Crossref PubMed Google Scholar The causes of these abnormalities remain largely obscure. Patients with CVID have often been stratified on the basis of peripheral blood B- and T-cell phenotype (discussed below) and in vitro B-cell function, using a number of stimuli. In most cases, B cells of some subjects produce normal amounts of immunoglobulin in culture, others produce only IgM, and others are unable to produce any immunoglobulin at all.32Bryant A. Calver N.C. Toubi E. Webster A.D. Farrant J. Classification of patients with common variable immunodeficiency by B cell secretion of IgM and IgG in response to anti-IgM and interleukin-2.Clin Immunol Immunopathol. 1990; 56: 239-248Crossref PubMed Scopus (115) Google Scholar One recent analysis using flow cytometric phenotyping and measurement of kappa-deleting recombination excision circles (KRECs, see below) distinguished 5 possible subgroups or defects: (1) B-cell production, (2) early peripheral B-cell maturation or survival, (3) B-cell activation and proliferation, (4) germinal center, and (5) postgerminal center.33Driessen G.J. van Zelm M.C. van Hagen P.M. Hartwig N.G. Trip M. Warris A. et al.B-cell replication history and somatic hypermutation status identify distinct pathophysiologic backgrounds in common variable immunodeficiency.Blood. 2011; 118: 6814-6823Crossref PubMed Scopus (28) Google Scholar In some patients, calcium flux after activation of the B-cell receptor may be impaired (note that these correspond to low switched memory B cells) with expansion of the CD21low population (see Table III).34Foerster C. Voelxen N. Rakhmanov M. Keller B. Gutenberger S. Goldacker S. et al.B cell receptor-mediated calcium signaling is impaired in B lymphocytes of type Ia patients with common variable immunodeficiency.J Immunol. 2010; 184: 7305-7313Crossref PubMed Scopus (30) Google Scholar Others have demonstrated distinct signaling abnormalities in subpopulations with CVID. For example, stimulation of B cells and/or plasmacytoid dendritic cells via Toll-like receptors 7, 8, and 9 is inhibited in some patients; this correlates with lower levels of switched memory B cells.35Marron T.U. Yu J.E. Cunningham-Rundles C. Toll-like receptor function in primary B cell defects.Front Biosci (Elite Ed). 2012; 4: 1853-1863Crossref PubMed Google ScholarTable IIIClassification schemes defining subgroups of patients with CVID on the basis of flow cytometric B-cell immunophenotyping∗Adapted from Wehr et al.29Nearly absent B cells (<1%†Expressed as a percentage of total B cells (CD19+ or CD20+).)Includes all patients with severe defects in B-cell differentiationLow switched memory B cells ( 9%)CD38hiIgMhiAssociated with lymphadenopathyExpansion of CD21low B cells (>10%)Associated with splenomegalyICOS, Inducible T cell co-stimulator.∗ Adapted from Wehr et al.29Wehr C. Kivioja T. Schmitt C. Ferry B. Witte T. Eren E. et al.The EUROclass trial: defining subgroups in common variable immunodeficiency.Blood. 2008; 111: 77-85Crossref PubMed Scopus (277) Google Scholar† Expressed as a percentage of total B cells (CD19+ or CD20+). Open table in a new tab ICOS, Inducible T cell co-stimulator. A relative loss of T-cell function in many subjects has been demonstrated, including a lack of circulating CD4 T cells,9Malphettes M. Gerard L. Carmagnat M. Mouillot G. Vince N. Boutboul D. et al.Late-onset combined immune deficiency: a subset of common variable immunodeficiency with severe T cell defect.Clin Infect Dis. 2009; 49: 1329-1338Crossref PubMed Scopus (64) Google Scholar and especially, naive CD4 T cells,36Giovannetti A. Pierdominici M. Aiuti F. T-cell homeostasis: the dark(ened) side of common variable immunodeficiency.Blood. 2008; 112 (author reply 446–7): 446Crossref PubMed Google Scholar antigen-specific T cells,37Funauchi M. Farrant J. Moreno C. Webster A.D. Defects in antigen-driven lymphocyte responses in common variable immunodeficiency (CVID) are due to a reduction in the number of antigen-specific CD4+ T cells.Clin Exp Immunol. 1995; 101: 82-88Crossref PubMed Google Scholar, 38Stagg A.J. Funauchi M. Knight S.C. et al.Failure in antigen responses by T cells from patients with common variable immunodeficiency (CVID).Clin Exp Immunol. 1994; 96: 48-53Crossref PubMed Google Scholar and impaired proliferation, activation,39Thon V. Eggenbauer H. Wolf H.M. Fischer M.B. Litzman J. Lokaj J. et al.Antigen presentation by common variable immunodeficiency (CVID) B cells and monocytes is unimpaired.Clin Exp Immunol. 1997; 108: 1-8Crossref PubMed Google Scholar and secretion of some cytokines (IL-2, IFN-γ, and IL-10)40Fischer M.B. Hauber I. Vogel E. Wolf H.M. Mannhalter J.W. Eibl MM. Defective interleukin-2 and interferon-gamma gene expression in response to antigen in a subgroup of patients with common variable immunodeficiency.J Allergy Clin Immunol. 1993; 92:
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