Langerhans Cell Histiocytosis Patients Have HLA Cw7 and DR4 Types Associated with Specific Clinical Presentations and No Increased Frequency in Polymorphisms of the Tumor Necrosis Factor Alpha Promoter

Background: Current theory on the etiology of Langerhans cell histiocytosis (LCH), formerly Histiocytosis-X, is that abnormality(ies) of the immune system are responsible for dysregulation of Langerhans cells (LC) in patients' lesions. Among the known abnormalities in LCH patients are increased amounts of tumor necrosis factor alpha (TNF-alpha) and other cytokines in the lesions.

Procedure: We investigated the human leukocyte antigen (HLA) phenotypes of 29 patients and 37 healthy family members to determine if any haplotypes segregate with the presence or locations of the disease. The lymphocyte subsets for 22 patients and 11 family members were also determined.

Results: Patients with single bone, multiple bone, or multi-system LCH had different relative proportions of HLA types. Patients presenting with single bone disease had an especially high frequency of the DR4 type. In this patient group, every Caucasian patient had either Cw7 or DR4. Lymphopenia was documented in patients who had been off therapy as well as those who only had surgical curetage of their lesions. Family members also had low numbers of T lymphocytes. There were fewer mutations of the TNF-alpha promoter in patients than in the general population.

Conclusions: Although there is an increased percentage of LCH patients with DR4 and/or Cw7 there was also an increased prevalence of this antigen as well as lymphopenia among unaffected family members. Additional genetic and/or environmental factors are necessary to explain this association. TNF-alpha promoter mutations are not responsible for the increased production of this cytokine.