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IL-12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL-12Rβ1 is a receptor chain of both the IL-12 and the IL-23 receptor and deficiency of IL-12Rβ1 thus abolishes both IL-12 and IL-23 signaling. IL-12Rβ1 deficiency is caused by bi-allelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL-12Rβ1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL-12Rβ1 protein. In addition to disease-causing mutations, rare and common variations with unknown functional effect have been reported in IL12RB1. All these variants have been deposited in the online IL12RB1 variation database (www.LOVD.nl/IL12RB1). In this article, we review the function of IL-12Rβ1 and molecular genetics of human IL12RB1.

The alloreactive human T cell clone MBM15 was found to exhibit dual specificity recognizing both an antigen in the context of the HLA class I A2 molecule and an antigen in the context of the HLA class II DR1. We demonstrated that the dual reactivity that was mediated via a single clonal T cell population depended on specific peptide binding. For complete recognition of the HLA-A2-restricted specificity the interaction of CD8 with HLA class I is essential. Interestingly, interaction of the CD8 molecule with HLA class I contributed to the HLA-DR1-restricted specificity. T cell clone MBM15 expressed two in-frame T cell receptor (TCR) V␣ transcripts (V␣1 and V␣2) and one TCR V␤ transcript (V␤13). To elucidate whether two TCR complexes were responsible for the dual recognition or one complex, cytotoxic T cells were transduced with retroviral vectors encoding the different TCR chains. Only T cells transduced with the TCR V␣1V␤13 combination specifically recognized both the HLA-A2 ؉ and HLA-DR1 ؉ target cells, whereas the V␣2V␤13 combination did not result in a TCR on the cell surface. T he function of the major histocompatibility complex (MHC) molecules is to bind and display peptides to T lymphocytes. Allogeneic MHC molecules can induce strong T cell responses, which is reflected by the mixed lymphocyte reaction in vitro and the high incidence of graft rejection and graft versus host disease after transplantation of organs or hematopoietic cells over MHC barriers. T cell recognition of allogeneic MHC is often peptide specific, resembling self-MHC-restricted T cell recognition of foreign antigens (1-3). However, alloreactive T cells are heterogeneous in their degree of peptide specificity (4), and a minor population might be peptide independent or recognize motifs shared by many peptides (5). Several alloreactive T cell clones have been described to be crossreactive, recognizing two unrelated peptides in the context of two different allogeneic MHC class I molecules (6, 7). In addition, alloreactive cytotoxic T lymphocytes recognizing an endogenously processed peptide binding to allogeneic MHC molecules and recognizing a different peptide in the context of self-MHC class I have been described (8). In one instance, crossreactive cytotoxic T lymphocytes showing dual recognition for both HLA class I and class II molecules also have been reported (9, 10). Those authors postulated that based on the shared structural motif between the HLA-B27 and the DR2 B5*0101 chain, the reactivity pattern reflected presentation of identical or structurally related peptides by HLA-B27 and HLA-DR2. In several of these previously mentioned studies, cold-target inhibition experiments were performed to confirm that one clonal T cell population was mediating the crossreactivity. However, whether the crossreactivity of these alloreactive T cell clones was mediated via one or two T cell receptor (TCR) ␣␤ complexes was not investigated. This hypothesis may be possible because 20% of peripheral human T cells and 10% of mouse T cells express two dif...

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Background: Tuberculosis (TB) remains a major threat to global health. Currently, diagnosis of active TB is hampered by the lack of specific biomarkers that discriminate active TB disease from other (lung) diseases or latent TB infection (LTBI). Integrated human gene expression results have shown that genes encoding complement components, in particular different C1q chains, were expressed at higher levels in active TB compared to LTBI.Methods: C1q protein levels were determined using ELISA in sera from patients, from geographically distinct populations, with active TB, LTBI as well as disease controls.Results: Serum levels of C1q were increased in active TB compared to LTBI in four independent cohorts with an AUC of 0.77 [0.70; 0.83]. After 6 months of TB treatment, levels of C1q were similar to those of endemic controls, indicating an association with disease rather than individual genetic predisposition. Importantly, C1q levels in sera of TB patients were significantly higher as compared to patients with sarcoidosis or pneumonia, clinically important differential diagnoses. Moreover, exposure to other mycobacteria, such as Mycobacterium leprae (leprosy patients) or BCG (vaccinees) did not result in elevated levels of serum C1q. In agreement with the human data, in non-human primates challenged with Mycobacterium tuberculosis, increased serum C1q levels were detected in animals that developed progressive disease, not in those that controlled the infection.Conclusions: In summary, C1q levels are elevated in patients with active TB compared to LTBI in four independent cohorts. Furthermore, C1q levels from patients with TB were also elevated compared to patients with sarcoidosis, leprosy and pneumonia. Additionally, also in NHP we observed increased C1q levels in animals with active progressive TB, both in serum and in broncho-alveolar lavage. Therefore, we propose that the addition of C1q to current biomarker panels may provide added value in the diagnosis of active TB.