Twin Boys with Major Histocompatibility Complex Class II Deficiency but Inducible Immune Responses

Wolf, Hermann M.; Hauber, Ilona; Gulle, Heinz; Thon, Vojtěch; Eggenbauer, H.; Fischer, Michael B.; Fiala, Sabine; Eibl, Martha M.

doi:10.1056/nejm199501123320204

Cited by 28 publications

(16 citation statements)

References 22 publications

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“…MHC II-deficient patients with mild clinical presentation have previously been reported, e.g., the 7-year-old KER twins. Their T cells were able to respond in vivo to antigenic challenge (13,14). Although the molecular basis of the MHC II defect was not elucidated in these twins, the Sa patients do not share the same defects, because their cells complemented the KER cell line for MHC-II expression.…”

Section: Discussionmentioning

confidence: 99%

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Mutation in the Class II trans-Activator Leading to a Mild Immunodeficiency

Wiszniewski¹,

Fondanèche²,

Deist³

et al. 2001

The Journal of Immunology

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The expression of MHC class II molecules is essential for all Ag-dependent immune functions and is regulated at the transcriptional level. Four trans-acting proteins control the coordinate expression of MHC class II molecules: class II trans-activator (CIITA), regulatory factor binding to the X box (RFX)-associated protein; RFX protein containing ankyrin repeats, and RFX5. In humans, defects in these genes result in MHC class II expression deficiency and cause combined immunodeficiency. Most patients with this deficiency suffer from severe recurrent infections that frequently lead to death during early childhood. We investigated three sisters, now ages 21, 22, and 24 years, in whom MHC-II deficiency was detected. Even though the eldest sibling was asymptomatic and the other two had only mild immunodeficiency, none of the three class II isotypes was expressed on T cell blasts, fibroblasts, EBV B cell lines, or epidermal dendritic cells. Residual HLA-II expression was detected in fresh PBMC. Somatic complementation identified the disease as CIITA deficiency. A homozygous T1524C (L469P) substitution was found in the coding region of the CIITA cDNA and was shown to be responsible for the defect in MHC-II expression. This missense mutation prevents the normal functioning of MHC-II but does not lead to the nuclear exclusion of the L469P CIITA. Transfection experiments demonstrated that the CIITA L469P mutant had residual MHC class II trans activation activity, which might explain the unusual clinical course of the patients studied. This study shows that an attenuated clinical phenotype or an asymptomatic clinical course can be observed in patients despite a profound defect in the expression of MHC class II genes. The frequency of the inherited MHC class II deficiency might thus be underestimated.

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Section: Discussionmentioning

confidence: 99%

“…KER B cell lines (13,14) from the patients were also used. Phenotypic complementation was tested by immunofluorescence 48 -72 h after cell fusion.…”

Section: Somatic Complementation Analysismentioning

confidence: 99%

Mutation in the Class II trans-Activator Leading to a Mild Immunodeficiency

Wiszniewski¹,

Fondanèche²,

Deist³

et al. 2001

The Journal of Immunology

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“…It also appears that the four complementation groups account for all currently known types of true MHC class II deficiency (Table 1). A family with an almost asymptomatic form of immunodeficiency and with only selective defects in the expression of certain HLA class II genes has been described, 28,29 but this atypical phenotype probably represents a distinct syndrome.…”

Section: Additional Defects In the Regulatory Gene Rfxapmentioning

confidence: 99%

Mutation of RFXAP, a Regulator of MHC Class II Genes, in Primary MHC Class II Deficiency

Villard¹,

Lisowska-Grospierre²,

Elsen³

et al. 1997

N Engl J Med

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“…In contrast to patients belonging to complementation groups A–D, the twin brothers show a relatively benign clinical symptomatology and are able to mount MHC class II‐dependent T‐cell responses and T‐dependent antibody responses after vaccination, e.g. with tetanus toxoid (Wolf et al , 1995). However, similar to all other patients, MHC class II expression was undetectable on the surface of peripheral blood B cells, monocytes and activated T cells, so that the cell type responsible for antigen presentation in the patients remained to be defined.…”

mentioning

confidence: 99%

“…Our results show residual surface membrane expression of functional MHC class II molecules on epidermal Langerhans cells and monocyte‐derived dendritic cells, but not on B cells, monocytes or activated T cells, indicating a cell‐specific defect of MHC class II expression. Furthermore, HLA‐DR expression was inducible by interferon‐γ (IFN‐γ) on DMEC but not on skin fibroblasts or peripheral blood monocytes (Wolf et al , 1995), indicating that the defect also impairs IFN‐γ‐mediated upregulation of MHC class II expression in a cell‐type‐specific manner.…”

mentioning

confidence: 99%

Residual expression of functional MHC class II molecules in twin brothers with MHC class II deficiency is cell type specific

Wolf¹,

Thon²,

Gulle³

et al. 2001

Br J Haematol

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Summary. We examined major histocompatibility complex (MHC) class II expression in B cells, peripheral blood monocytes, activated T cells, epidermal Langerhans cells, monocyte-derived dendritic cells, dermal microvascular endothelial cells (DMEC) and fibroblasts of twin brothers with MHC class II deficiency. Although residual human leucocyte antigen (HLA)-DR expression was found on a subpopulation of epidermal Langerhans cells and a subset of peripheral blood monocyte-derived dendritic cells, the patients' B cells, monocytes and activated T cells were HLA-DR negative. After treatment with interferon-g (IFNg), the patients' DMEC expressed HLA-DR but not -DP and -DQ at the protein and mRNA level, whereas IFN-g failed to induce HLA-DR expression on dermal fibroblasts. The patients' monocyte-derived dendritic cells were capable of processing and presenting tetanus toxoid to autologous T cells, and patient-derived DMEC induced the proliferation of allogeneic CD41 T cells in an MHC class II-restricted fashion, indicating that the observed residual MHC class II surface expression was functional. The findings reported show that the defect encountered in these patients is not necessarily expressed to the same extent in different cell lineages, which is relevant for the understanding of the patients' phenotype and also illustrates that only small amounts of MHC class II are needed to mount a functional cellular immune response in vivo.

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Twin Boys with Major Histocompatibility Complex Class II Deficiency but Inducible Immune Responses

Cited by 28 publications

References 22 publications

Mutation in the Class II trans-Activator Leading to a Mild Immunodeficiency

Mutation in the Class II trans-Activator Leading to a Mild Immunodeficiency

Mutation of RFXAP, a Regulator of MHC Class II Genes, in Primary MHC Class II Deficiency

Residual expression of functional MHC class II molecules in twin brothers with MHC class II deficiency is cell type specific

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