Immune deficiency, autoimmune disease and intellectual disability: A pleiotropic disorder caused by biallelic variants in the TPP2 gene.

Four individuals from two families presented with a multisystemic condition of suspected genetic origin that was diagnosed only after genome analysis. The main phenotypic features were immune system dysregulation (severe immunodeficiency with autoimmunity) and intellectual disability. The four individuals were found to be homozygous for a 4.4 Kb deletion removing exons 20-23 (NM_003291.4) of the TPP2 gene, predicting a frameshift with premature termination of the protein. The deletion was located on a shared chromosome 13 haplotype indicating a Swiss founder mutation. Tripeptidyl peptidase 2 (TPP2) is a protease involved in HLA/antigen complex processing and amino acid homeostasis. Biallelic variants in TPP2 have been described in 10 individuals with variable features including immune deficiency, autoimmune cytopenias, and intellectual disability or chronic sterile brain inflammation mimicking multiple sclerosis. Our observations further delineate this severe condition not yet included in the OMIM catalog. Timely recognition of TPP2 deficiency is crucial since (1) immune surveillance is needed and hematopoietic stem cell transplantation may be necessary, and (2) for provision of genetic counselling. Additionally, enzyme replacement therapy, as already established for TPP1 deficiency, might be an option in the future.

IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation.

BACKGROUND: Data on patients affected by chronic mucocutaneous candidiasis underscore the preponderant role of IL-17 receptor A (IL-17RA) in preserving mucocutaneous immunity. Little is known about the role of adenosine deaminase (ADA) 2 in regulation of immune responses, although recent reports linked ADA2 deficiency with inflammation and vasculitis. OBJECTIVE: We sought to investigate the mechanisms of chronic inflammation and vasculitis in a child lacking IL-17RA and ADA2 to identify therapeutic targets. METHODS: We report a family with 2 siblings who have had recurrent mucocutaneous infections with Candida albicans and Staphylococcus aureus and chronic inflammatory disease and vasculitis since early childhood, which were refractory to classical treatments. Array-based comparative genomic hybridization analysis showed that both siblings are homozygous for a 770-kb deletion on chr22q11.1 encompassing both IL17RA and cat eye critical region 1 (CECR1). Immunologic studies were carried out by means of flow cytometry, ELISA, and RIA. RESULTS: As expected, in the affected child we found a lack of IL-17RA expression, which implies a severe malfunction in the IL-17 signaling pathway, conferring susceptibility to recurrent mucocutaneous infections. Surprisingly, we detected an in vitro and in vivo upregulation of proinflammatory cytokines, notably IL-1ß and TNF-α, which is consistent with the persistent systemic inflammation. CONCLUSIONS: This work emphasizes the utility of whole-genome analyses combined with immunologic investigation in patients with unresolved immunodeficiency. This approach is likely to provide an insight into immunologic pathways and mechanisms of disease. It also provides molecular evidence for more targeted therapies. In addition, our report further corroborates a potential role of ADA2 in modulating immunity and inflammation.

Genotypes of p53 codon 72 correlate with age at onset of type 1 diabetes in a sex-specific manner.

In type 1 diabetes mellitus (T1D) p53 pathways are up-regulated and there is an increased susceptibility to apoptosis. The hypothesis is that p53 codon 72 polymorphism could be associated with T1D. A total of 286 children with T1D and a control sample of 730 subjects were studied. p53 codon 72 polymorphism was analysed by polymerase chain reaction. A large increase of p53 *Arg/*Arg was observed in T1D patients with age at onset < 6 years. A strong linear correlation between *Arg/*Arg genotype and age at onset was observed in females. The involvement of the *Arg/*Arg genotype in apoptosis suggests that during the autoimmune process leading to T1D, genetic factors that favor apoptosis may contribute to the onset of overt disease.

Ligation of CD46 to CD40 inhibits CD40 signaling in B cells.

CD40 induces B cells to switch to IgE in the presence of IL-4 and up-regulates their expression of the low-affinity receptor for IgE, CD23, which promotes the immune response to allergen complexed with IgE antibody. CD40 binds to CD40L and to the C4b-binding protein (C4BP) using distinct sites. CD46 is a receptor for the product of activated complement C4b. Some microbial antigens bind both C4BP and CD46, potentially bridging CD40 to CD46. In addition, immune complexes containing both C4b and C4BP may cross-link CD40 to CD46. We demonstrate that cross-linking CD46 to CD40 on B cells inhibits CD40-mediated up-regulation of surface CD23 expression and induction of IL-4-dependent IgE isotype switching. This was associated with inhibition of induction of Cε germ line transcripts and of activation-induced cytidine deaminase mRNA expression. Furthermore, co-ligation of CD46 to CD40 blocked CD40-mediated NF-κB activation. These observations suggest that complement components may play an important role in regulating CD40 activation of B cells and the allergic response.

Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue.

A missense C1858T single nucleotide polymorphism in the PTPN22 gene recently emerged as a major risk factor for human autoimmunity. PTPN22 encodes the lymphoid tyrosine phosphatase (LYP), which forms a complex with the kinase Csk and is a critical negative regulator of signaling through the T cell receptor. The C1858T single nucleotide polymorphism results in the LYP-R620W variation within the LYP-Csk interaction motif. LYP-W620 exhibits a greatly reduced interaction with Csk and is a gain-of-function inhibitor of signaling. Here we show that LYP constitutively interacts with its substrate Lck in a Csk-dependent manner. T cell receptor-induced phosphorylation of LYP by Lck on an inhibitory tyrosine residue releases tonic inhibition of signaling by LYP. The R620W variation disrupts the interaction between Lck and LYP, leading to reduced phosphorylation of LYP, which ultimately contributes to gain-of-function inhibition of T cell signaling.

Induction of anergic allergen-specific suppressor T cells using tolerogenic dendritic cells derived from children with allergies to house dust mites.

BACKGROUND: Dendritic cells (DCs) regulate the immune response to allergens in the lung; they induce either effector or regulatory T cells, which promote or suppress, respectively, the development of allergy. IL-10 is a potent immunosuppressive cytokine that induces type 1 regulatory (Tr1) T cells. OBJECTIVE: To generate allergen-specific Tr1 cells in vitro from children with allergy. METHODS: Monocyte-derived DCs from children with allergy to house dust mites (HDM) were generated by incubating the cells with IL-10 and pulsing them with Der p 2, a major HDM allergen, or by pulsing them with Der p 2 and incubating them with IL-10 during their last 2 days of differentiation. RESULTS: Der p 2-specific T-cell proliferation and T(H)2 cytokine production were significantly reduced when T cells from patients with allergy to HDM were activated with autologous Der p 2-pulsed DCs that had been differentiated or incubated with IL-10. T-cell lines generated with Der p 2-pulsed DCs that were differentiated with IL-10 were hyporesponsive to reactivation with Der p 2 and able to suppress Der p 2-specific T(H)2 effector cells. CONCLUSION: Dendritic cells differentiated in the presence of IL-10 and pulsed with allergen gave rise to a population of tolerogenic DCs that induced allergen-specific Tr1 cells. This finding represents an important step forward to the prospective clinical application of tolerogenic DCs to modulate allergen-specific T-cell responses.

C4b-binding protein (C4BP) activates B cells through the CD40 receptor.

We demonstrate that the alpha chain of human C4b binding protein (C4BP) binds directly to CD40 on human B cells at a site that differs from that used by CD40 ligand. C4BP induces proliferation, upregulation of CD54 and CD86 expression, and IL4-dependent IgE isotype switching in normal B cells but not in B cells from patients with CD40 or IKKgamma/NEMO deficiencies. Furthermore, C4BP colocalized with B cells in the germinal centers of human tonsils. These observations suggest that C4BP is an activating ligand for CD40 and establish a novel interface between complement and B cell activation.