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

为了产生抗体，需要B细胞分化为分泌抗体的细胞，即浆细胞。我们描述了CD27的结扎，它属于肿瘤坏死因子受体（TNFR）家族，是B细胞的记忆标记物，是记忆B细胞标记物，并产生积极控制B细胞进入浆细胞通路的关键信号。在此基础上，我们研究了b细胞在血清低水平免疫球蛋白原发性免疫缺陷中的功能，为原发性免疫缺陷的诊断和治疗提供了新的思路。我们描述了一种新的基因组外显子3缺失突变，导致Artemis基因外显子3和4 m RNA跳变，在4个不相关家族的4名日本患者中发现，他们患有严重的联合免疫缺陷，缺乏免疫球蛋白和增加细胞放射敏感性（RS-SCID）。在他们的父母中也发现了杂合性的基因外显子3缺失。这是东亚地区首次对阿尔忒弥斯基因缺乏的研究，表明阿尔忒弥斯基因突变是日本特有的。在共同可变免疫缺陷方面，共同可变免疫缺陷（CVID）的分子基础尚不清楚。为了评估CVID的体液免疫，我们选择了24例早发或晚发疾病的患者。根据临床表型、免疫反应评估、单核细胞或血小板中布鲁顿酪氨酸激酶（Btk）的存在以及活化T细胞CD40配体的正常表达，排除x -连锁无球蛋白血症（XLA）、x -连锁高igm综合征（XHIM）和非XHIM。循环B细胞数量在正常范围内或减少。24例患者IgD^- CD27^+记忆B细胞均明显减少或缺失，8例患者IgD^+ CD27^+记忆B细胞减少。来自所有6名患者的循环B细胞，包括IgD^+ CD27^+细胞的CVID患者，在免疫球蛋白可变(V)区基因中没有发生体细胞高突变，类似于脐带血B细胞。CVID患者的B细胞在IL-2和IL-10存在的情况下，在Ig受体和CD40的作用下产生IgM和IgG，但不产生IgA。除5例患者外，其余患者的B细胞在JL-4存在下受CD40交联刺激时均分泌IgE。对具有异常细胞标记物表达和功能的记忆缺陷B细胞的观察表明，幼稚CVID B细胞，包括那些表达IgD^+ CD27^+的细胞，类似于脐带血和高IgM综合征B细胞，可能导致它们无法分化为浆细胞并产生不同同型的高亲和力抗体。在x连锁高IgM综合征（XHIM）患者中，来自大多数患者的单个核细胞的共刺激诱导无到低水平的从IgM到IgG和IgA的转换，与金黄色葡萄球菌Cowan菌株（SAC）加IL-2或抗cd40单抗（抗cd40）加IL-10。部分患者在抗cd40 + IL-4刺激后可分泌可测量水平的IgE。SAC + IL-2 +抗cd40 + IL-10的共刺激产生除IgM外显著水平的IgG，但不分泌IgA。最引人注目的发现是，所有6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细胞明显减少。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产生的低反应是由于IgD- CD27+记忆B细胞数量减少。然而，在体外，免疫球蛋白受体和CD40与IL-2、IL-10等细胞因子协同刺激可诱导IgG的产生。少

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