GENETIC ASPECTS OF IMMUNODEFICIENCY

X连锁免疫缺陷携带者-严重合并 免疫缺陷(SCID)、Wiskott-Aldrich综合征、高IgM 综合征和X连锁淋巴增殖性综合征-是正常的 由所有免疫学参数决定。我们建议， 这些专性杂合子表现出任何这些迹象 疾病是由于选择性使用X染色体造成的 在所有受影响的细胞系中不携带作为活性X的基因缺陷 由基因缺陷引起。如果这一假设是正确的，那么 允许区分活跃和不活跃的X染色体 将允许识别受该基因影响的细胞系 并为这些缺陷的载体检测提供了依据 精神错乱。我们最近开发了一种这样的技术。体细胞 纯化的T细胞、B细胞、NK细胞产生细胞杂交体 来自高危女性和中国仓鼠的细胞或单核细胞 缺乏X-连接酶HGPRT的细胞系。 容易丢失人类染色体的杂交种是在 有选择性的媒体，只有那些保留了 活跃的人类X染色体将存活下来。从这些DNA中提取 使用X连锁的限制性片段长度对杂交进行分析 女性为杂合子的多态(RFLP)。如果 用于制造杂交细胞的细胞谱系不受 基因缺陷，或者如果研究的女性不是 有问题的疾病，大约一半的杂交将使用 母系衍生的X染色体作为活跃的X和一半将 使用父系派生的那个。然而，如果被研究的女性是 携带者和所研究的细胞谱系受到基因的影响 缺陷，那么所有的混血儿都会使用 不携带基因缺陷为活性X(非随机X 染色体失活)。我们打算使用这项技术来 确定受所列基因缺陷影响的细胞系 并为这些疾病提供携带者检测。我们的 初步研究将侧重于以下X连锁SCID 原因：1)确定受该疾病影响的细胞系 将特别有助于澄清两者之间的关系 参与免疫反应的各种细胞系；2)有 X连锁SCID的临床或实验室特征是否 将其与其他形式的SCID区分开来，使知情基因 咨询困难；3)我们识别X-病毒携带者的能力- 关联的SCID将增加提供信息的个人数量 受影响的家系，从而使我们更容易绘制这一地图 无序。

Carriers of the X-linked immunodeficiencies - severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, hyper-IgM syndrome and X-linked lymphoproliferative syndrome-are normal by all immunologic parameters. We propose that the failure of these obligate heterozygotes to demonstrate any sign of these disorders is due to selective use of the X chromosome that does not carry the gene defect as the active X in all cell lines affected by the gene defect. If this hypothesis is correct, techniques that permit the distinction of the active and inactive X chromosomes will allow identification of the cell lines affected by the gene defects and provide a basis for carrier detection assays in these disorders. We have recently developed such a technique. Somatic cell hybrids are produced between purified T cells, B cells, NK cells or monocytes from a woman at risk and a chinese hamster cell line that is deficient in the X-linked enzyme HGPRT. Hybrids, which tend to lose human chromosomes, are grown in selective media so that only those hybrids that have retained the active human X chromosome will survive. DNA from these hybrids is analyzed, using an X-linked restriction fragment length polymorphism (RFLP) for which the woman is heterozygous. If the cell lineage used to make the hybrids is not affected by the gene defect, or if the woman studied is not a carrier of the disease in question, approximately half of the hybrids will use the maternally derived X chromosome as the active X and half will use the paternally derived one. However, if the woman studied is a carrier and the cell lineage studied is affected by the gene defect, then all the hybrids will use the X chromosome that does not carry the gene defect as the active X (non-random X chromosome inactivation). We intend to use this technique to determine the cell lineages affected by the gene defects listed above, and to provide carrier detection for these disorders. Our initial studies will focus on X-linked SCID for the following reasons: 1) determining the cell lines affected by this disorder will be particularly useful in clarifying the relationships between the various cell lines involved in the immune response; 2) there are no clinical or laboratory characteristics of X-linked SCID that distinguish it from other forms of SCID, making informed genetic counseling difficult; and 3) our ability to identify carriers of X- linked SCID will increase the number of informative individuals in affected pedigrees and thereby make it easier for us to map this disorder.