Analysis of primary immunodeficiency syndrome with low levels of antibody: diagnosis and treatment

原发性免疫缺陷综合征低抗体分析：诊断与治疗

• 批准号: 13470162
• 负责人: KOMIYAMA Atsushi
• 金额: $ 5.57万
• 依托单位: Shinshu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470162/
• 关键词: Plasma cells; Memory B cells; CD27; immunodeficiency; Naive B cells; 抗体欠乏; 重症複合免疫不全症; 分類不能型免疫不全症; 遺伝子治療

To produce antibodies, the differentiation of B cells into antibody-secreting cells, plasma cells, is required. We describe that a ligation of CD27, which belongs to the tumor necrosis factor receptor (TNFR) family and is memory marker of B cells, is memory B-cell marker and yields crucial signals that positively control the entry of B cells into the pathway to plasma cells. On the basis of this finding, we investigated B-cell functions in primary immunodeficiencies with low levels of immunoglobulins in the serum, and performed new approach about the diagnosis and the treatment in primary immunodeficiencies.we describe a novel mutation of genomic exon 3 deletion, resulting in exon 3 and 4 m RNA skipping, of Artemis gene found in 4 Japanese patients of 4 unrelated families with severe combined immunodeficiency with absence of immunoglobulin and increased cellular radiosensitivity (RS-SCID) . The heterozygous genornic exon 3 deletion was also found in their parents studied. This report i … More s the first study of Artemis deficiency in East Asia and suggests that the Artemis gene mutation is peculiar to Japanese.In regarding common variable immunodeficiency, The molecular basis of common variable immunodeficiency (CVID) is unknown. To assess humoral immunity in CVID, we selected 24 patients with early or late onset of disease. X-linked agammaglobulinemia (XLA), X-linked hyper-IgM syndrome (XHIM) and non-XHIM were excluded based on clinical phenotype, assessment of the immune response, presence of Bruton's tyrosine kinase (Btk) in monocytes or platelets and normal expression of CD40 ligand by activated T cells. The number of circulating B cells was within normal range or reduced. IgD^- CD27^+ memory B-cells were markedly reduced or absent in all 24 patients and IgD^+ CD27^+ B cells were diminished in 8 patients. Circulating B cells from all six patients examined, including CVID patients with IgD^+ CD27^+ cells, failed to undergo somatic hypermutation in immunoglobulin variable (V)-region genes, similar to cord blood B cells. B cells from CVID patients produced IgM and IgG, but not IgA upon the engagement of Ig receptor and CD40 in the presence of IL-2 and IL-10. B cells from all but 5 patients secreted IgE when stimulated by CD40 crosslinking in the presence of JL-4. The observation of defective memory B cells with abnormal cell marker expression and function demonstrates that naive CVID B cells including those expressing IgD^+ CD27^+, in analogy to cord blood and hyper IgM syndrome B cells, may be responsible for their failure to differentiate into plasma cells and to produce high affinity antibodies of different isotypes.In the patients with X-linked hyper-IgM syndrome (XHIM), costimulation of mononuclear cells from most of the patients induced no to low levels of class switching from IgM to IgG and IgA with Staphylococcus aureus Cowan strain (SAC) plus IL-2 or anti-CD40 mAb (anti-CD40) plus IL-10. Measurable levels of IgE were secreted in some of the patients after stimulation with anti-CD40 plus IL-4. Costimulation with SAC plus IL-2 plus anti-CD40 plus IL-10 yielded secretion of significant levels of IgG in addition to IgM, but not IgA. The most striking finding was that peripheral blood B cells from all of the six patients were composed of only IgD+ CD27- and IgD+ CD27+ B cells; IgD- CD27+ memory B cells were greatly decreased. IgD+ CD27+ B cells from an XHIM patient produced IgM predominantly. Our data indicate that the low response of IgG production in XHIM patients is due to reduced numbers of IgD- CD27+ memory B cells . However, the IgG production can be induced by stimulation of immunoglobulin receptors and CD40 in cooperation with such cytokines as IL-2 and IL-10 in vitro. Less

为了产生抗体，需要将B细胞分化为分泌抗体细胞，血浆细胞。我们描述的是，CD27的连接属于肿瘤坏死因子受体（TNFR）家族，是B细胞的记忆标记，是内存B细胞标记物，产生了关键信号，可积极控制B细胞进入plasma细胞的途径。根据这一发现，我们研究了血清中免疫球蛋白水平较低的原发性免疫缺陷的B细胞功能，并在原发性免疫缺陷中采取了有关诊断和治疗的新方法免疫缺陷，没有免疫球蛋白和增加的细胞放射敏性（RS-SCID）。在他们的父母研究中，还发现了杂合型外显子3缺失。这份报告i…更多是东亚artemis缺乏症的首次研究，并表明Artemis基因突变是日语特有的。在公共可变免疫缺陷方面，常见可变免疫缺陷（CVID）的分子基础尚不清楚。为了评估CVID中的体液免疫组织化学，我们选择了24例疾病早期或晚期发作的患者。基于临床表型，评估免疫激素的评估，在单囊细胞或正常表达中，X连接的Agammagaglobulinemia（XLA），X连接的高IGM综合征（XHIM）和非XHIM被排除在临床表型中，评估免疫响应，Bruton的酪氨酸激酶（BTK）和正常表达中的表达。循环B细胞的数量在正常范围内或减少。 IgD^-CD27^+记忆B细胞在所有24例患者中显着降低或吸收，IgD^+ CD27^+ B细胞在8例患者中减少。来自所有检查的六名患者的循环B细胞，包括患有IGD^+ CD27^+细胞的CVID患者，在免疫球蛋白可变（V） - 区域基因中未能经过体细胞超数，类似于脐带血B细胞。 CVID患者的B细胞在IL-2和IL-10的存在下Ig受体和CD40的参与后产生了IgM和IgG，而不是IgA。当JL-4存在的CD40刺激CD40刺激时，来自除5例患者的B细胞分泌IgE。 The observation of defective memory B cells with abnormal cell marker expression and function demonstrates that naive CVID B cells including those expressing IgD^+ CD27^+, in analogy to cord blood and hyper IgM syndrome B cells, may be responsible for their failure to differentiate into plasma cells and to produce High affinity antibodies of different isotypes.In the patients with X-linked hyper-IgM syndrome (XHIM), costimulation of来自大多数患者的单核细胞通过金黄色葡萄球菌Cowan菌株（SAC）加上IL-2或IL-2或抗CD40 MAB（抗CD40）和IL-10诱导从IgM转换为IgG和IgA的较低水平的类别。抗CD40加IL-4刺激后，一些患者分泌了可测量的IgE水平。与SAC Plus IL-2加抗CD40加IL-10的共刺激除了IgM外，还可以分泌显着水平的IgG，而不是IgA。最引人注目的发现是，来自所有六名患者的外周血B细胞仅由IGD+ CD27-和IGD+ CD27+ B细胞组成。 IGD-CD27+记忆B细胞大大减少。来自XHIM患者的IgD+ CD27+ B细胞主要产生IgM。我们的数据表明，XHIM患者IgG产生的反应较低是由于IgD-CD27+记忆B细胞数量减少。然而，可以通过与IL-2和IL-10的细胞因子合作刺激免疫球蛋白受体和CD40刺激IgG产生。较少的

项目成果

nagumo H, Agematsu K, Kobayashi N, Shinozaki S, Hokibara S, Nagase H, Takamoto M, Yasui K, Sugane S, Komiyama A: "Different process of class switching and somatic hypermutation : a novel analysis by CD27^- naive B cells"Blood. 15. 567-575 (2002)

nagumo H, Agematsu K, Kobayashi N, Shinozaki S, Hokibara S, Nagase H, Takamoto M, Yasui K, Sugane S, Komiyama A：“类别转换和体细胞超突变的不同过程：CD27^-幼稚 B 细胞的新分析

Gombart A.F., Shiohara M., Kwok S.H., Agematsu K., Komiyama A., Koeffier H.P.: "Neutrophil-specific granule deficiency: homozygous recessive inheritance of a frameshift mutation in the gene encoding transcription factor CCAAT/enhancer binding protein-epsi

Gombart A.F.、Shiohara M.、Kwok S.H.、Agematsu K.、Komiyama A.、Koeffier H.P.：“中性粒细胞特异性颗粒缺陷：编码转录因子 CCAAT/增强子结合蛋白-epsi 的基因中移码突变的纯合隐性遗传

Uehara Y, Kikuchi K, Nakamura T, Nakama H, Agematsu K, Kawakami Y, Maruchi N, Totsuka K: "H202 Produced by Viridans Group Streptococci May Contribute to Inhibition of Methicillin-Resistant Staphylococcus aureus Colonization of Oral Cavities in Newborns"Cl

Uehara Y、Kikuchi K、Nakamura T、Nakama H、Agematsu K、Kawakami Y、Maruchi N、Totsuka K：“Viridans 群链球菌产生的 H202 可能有助于抑制新生儿口腔中耐甲氧西林金黄色葡萄球菌的定植”Cl

Yamada S, Shinozaki K, Agematsu K.: "Involvement of CD27/CD70 interactions in antigen-specific cytotoxic T-lymphocyte(CTL)activity by perforin-mediated cytotoxicity"Clin Exp Immunol. 130. 424-430 (2002)

Yamada S、Shinozaki K、Agematsu K.：“穿孔素介导的细胞毒性导致 CD27/CD70 相互作用参与抗原特异性细胞毒性 T 淋巴细胞 (CTL) 活性”Clin Exp Immunol。

Nagumo H, Agematsu K, Kobayashi N, Shinozaki S, Hokibara S, Nagase H, Takamoto M, Yasui K, Sugane S, Komiyama A: "Different process of class switching and somatic hypermutation ; a novel analysis by CD27^-naive B cells"Blood. 99. 567-575 (2002)

Nagumo H、Agematsu K、Kobayashi N、Shinozaki S、Hokibara S、Nagase H、Takamoto M、Yasui K、Sugane S、Komiyama A：“类别转换和体细胞超突变的不同过程；CD27^-naive B 细胞的新分析