GENETIC ASPECTS OF IMMUNODEFICIENCY

X-连锁免疫缺陷携带者-严重联合 免疫缺陷（SCID），Wiskott-Aldrich综合征，高IgM 综合征和X-连锁淋巴增生综合征-是正常的 所有的免疫参数。 我们认为， 这些专性杂合子，以证明任何迹象，这些 疾病是由于选择性使用X染色体， 在所有受影响的细胞系中不携带活性X基因缺陷 基因缺陷。 如果这个假设是正确的， 允许区分活跃和不活跃的X染色体 将允许鉴定受基因影响的细胞系 缺陷，并提供了在这些载体检测测定的基础 紊乱 我们最近开发了这样一种技术。 体细胞 在纯化的T细胞、B细胞、NK细胞和NK细胞之间产生细胞杂交体。 细胞或单核细胞从一个女人在风险和中国仓鼠 缺乏X-连锁酶HGPRT的细胞系。 杂交种往往会丢失人类的染色体， 选择性培养基，只有那些保留了 活跃的人类X染色体将存活下来。 DNA从这些 杂交分析，使用X连锁限制性片段长度 多态性（RFLP），女性是杂合子。 如果 用于制造杂交体的细胞谱系不受 基因缺陷，或者如果研究的女性不是基因缺陷的携带者， 疾病的问题，大约一半的杂交将使用 母源性X染色体作为活跃的X和半将 使用父系派生的一个。 然而，如果被研究的女性是 携带者和研究的细胞谱系受该基因的影响 那么所有的混血儿都会使用X染色体 不携带基因缺陷作为活性X（非随机X 染色体失活）。 我们打算用这种技术 确定受所列基因缺陷影响的细胞谱系 以上，并提供这些疾病的载体检测。 我们 最初的研究将集中在X连锁的SCID， 原因：1）确定受这种疾病影响的细胞系 将特别有助于澄清 参与免疫反应的各种细胞系; 2）有 X连锁SCID没有临床或实验室特征， 将其与其他形式的SCID区分开来，使知情的遗传学 咨询困难; 3）我们识别X-携带者的能力- 链接的SCID将增加信息个体的数量， 从而使我们更容易绘制出 disorder.

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.