Relative Impact of Hla Phenotype and Cd4–Cd8 Ratios on the Clinical Expression of Hemochromatosis

Abstract

erogeneous clinical expression. It is becoming increasingly Hemochromatosis is a hereditary iron-overload disevident that the ''clinical scene'' of diagnosis of hemochromaease linked to HLA. The clinical expression of hemochrotosis is changing 5 with less severe, or even asymptomatic, matosis is influenced by sex and age. However, other forms of the disease becoming increasingly frequent. This factors must account for the notorious heterogeneity of change is in part the result of the existence of an established expression of the disease independent of sex, age, and link between the disease and HLA. 6,7 HLA linkage studies HLA phenotype. The present study attempts to clarify have permitted localization of the putative hemochromatosis some of these additional factors based on exhaustive stagene in a short region around the HLA-A locus. [8][9][10] Therefore, tistical analysis of data collected from 43 selected pa-HLA phenotyping, by permitting the detection of cases tients with hemochromatosis. The statistical analysis fothrough family screening, allows identification of cases much cused on three groups of variables: the first group before the classical clinical symptoms develop. 11 To a certain included variables reflecting the clinical expression of extent, the latter development has exposed further the ignothe disease; the second group represented the biochemirance of the factors underlying the heterogeneity in presentacal and hematological values at the time of diagnosis; tion and progression of the disease. 12 and the third group consisted of the independent variIn the course of our early studies in hemochromatosis, disables sex, age, HLA phenotype, and T-cell subset profile, tinct clinical groups of patients could be defined with the i.e., the percentages and total numbers of CD4/ and different CD4-CD8 ratios and distinct responses to intensive CD8/ cells and the CD4-CD8 ratios. The results show phlebotomy treatment. 3,4 that the relative expansion of the two main T-cell sub-The present study consists of an extensive comparative sets, in the context of the HLA phenotype, correlates analysis of the relative impact of HLA phenotype and CD4-significantly with the clinical expression of hemochro-CD8 ratios on the clinical expression of the disease. Other matosis and the severity of iron overload. The present factors known for some time to influence presentation and findings substantiate further the postulate that T cells course of disease, namely sex and age, were also included. have a role in the regulation of iron metabolism. (HEPA-The results substantiate the existence of a significant associ-TOLOGY 1997;25:397-402.) ation between HLA phenotype, CD4-CD8 ratios, and clinical progression of the disease, illustrating the importance of a A recent study by Amadori et al. 1 showing considerable major histocompatibility complex (MHC) applying the princivariation in CD4-CD8 ratios in the normal population was ples discussed by Amadori et al. 1 to an class I-linked disease, received with a commentary stressing its ''se...

Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?

“…To our knowledge, this is the first demonstration of the impact of an HLA-A allele (HLA-A29) and a mutation in a non-classical MHC-class I gene located 4 Mb away (H63D) on lymphocyte numbers. The consistent finding of a phenotypic association between low lymphocyte numbers and high hepatic iron storage in HH patients (Porto et al 1997(Porto et al , 1998 and in lymphocyte-defective knockout mice (De Sousa et al 1994;Santos et al 1996Santos et al , 2000, led us to the present finding of significantly higher numbers of CD8 + T cells in HLA-A29 normal subjects carrying the H63D mutation. This observation may give us some insight into the mechanism whereby the lymphocytes could contribute to the regulation of iron metabolism.…”

“…Haplotype analysis in families of patients with iron overload HLA types and HFE genotypes from hemochromatosis patients and family members were accessed through the files from the Hemochromatosis Outpatient Clinic database at Santo António General Hospital, Porto, as described in previous studies (Porto et al 1997(Porto et al , 1998. For the present analysis we selected all families in which both HLA typing and HFE genotyping were available.…”

“…Total lymphocyte counts and those of CD4 + and CD8 + T cells from normal HLA and H63D-typed subjects included in previous studies Porto et al 1997Porto et al , 1998, were reviewed from the files of the Hemochromatosis Outpatient Clinic database at Santo António General Hospital, Porto. Exclusion criteria were the presence of positive viral markers for the following viruses: HCV, HBV, HIV I and II, and HTLV.…”

Major histocompatibility complex class I associations in iron overload: evidence for a new link between the HFE H63D mutation, HLA-A29, and non-classical forms of hemochromatosis

“…Peripheral CD8 + T lymphocytes are known to be activated and their numbers to be set in the context of MHC class I molecules Tanchot et al 1997). Abnormally low numbers of those cells have been found in HLA-A3 + HH patients with the most severe forms of iron overload (Porto et al 1997), and the same patients also showed abnormalities in the TCR repertoire of CD8 + , but not CD4 + T cells (Cabeda et al 1995).…”

“…Of those patients, 39 (25 unrelated probands and 14 family members) were genetically and clinically well-characterized HH patients according to previously described criteria (Porto et al 1997), and 25 (20 unrelated probands and 5 family members) were diagnosed as hemochromatosis patients based on biochemical and histological grounds but who did not fulfill the criteria to be classified as having genetic hemocromatosis, either because they had other associated clinical conditions (hematological disorders, chronic alcoholic or viral liver disease, disturbance of lipid metabolism), and/or showed lower levels of iron stores (55 g) estimated by quantitative phlebotomies. These patients were classified as having non-classical hemochromatosis (NCH).…”