Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS patients. We show that monocytes from VEXAS are quantitatively and qualitatively impaired and display features of exhaustion with aberrant expression of chemokine receptors. In peripheral blood from VEXAS patients, we identify an increase in circulating levels of many proinflammatory cytokines, including IL-1β and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirms these findings and also reveals a significant enrichment of TNF-α and NFκB signaling pathways that can mediate cell death and inflammation. This study suggests that the control of the nflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome.

The precise role of human epidermal Langerhans cells (LCs) in immune response is highly controversial. While studying the gene expression profile of these cells, we were intrigued to identify the HLA-DQB2 gene as potentially expressed in LCs. Despite a strong evolutionary conservation of their sequences, the concomitant expression of the poorly polymorphic HLA-DQA2/HLA-DQB2 genes, paralogous to the HLA-DQA1/HLA-DQB1 genes, has never been detected in any cell type. We confirmed by RT-PCR that the HLA-DQA2 and -DQB2 genes are both expressed in LCs, but not in monocyte-derived dendritic cells, or in blood CD1c⁺ or plasmacytoid dendritic cells. The presence of the HLA-DQβ2 chain in LCs could be demonstrated by Western blotting, whereas immunofluorescence revealed its localization in early endosomes. As in the case of other HLA class II molecules, the HLA-DQα2 and -DQβ2 chains formed heterodimers that had to associate with the invariant chain to reach endosomal compartments. HLA-DQα2/β2 heterodimers were expressed at the cell surface, where they could mediate staphylococcal superantigen stimulation of T cells. Interestingly, HLA-DQα2 and HLA-DQβ1 chains formed mixed heterodimers which efficiently left the endoplasmic reticulum. These observations strongly suggest that the poorly polymorphic HLA-DQA2 and -DQB2 genes should be considered to be of immunological importance. The HLA-DQα2/β2 molecules could influence the complexity of the repertoire of Ags presented by LCs.

When it comes to tick-borne diseases, co-infections are often mentioned. This concept includes several entities. On the one hand, tick vectors or vertebrate reservoir host can harbor several microorganisms that can be pathogenic for humans. On the other hand, human co-infections can also be understood in different ways, ranging from seropositivity without clinical symptoms to co-disease, i.e., the simultaneous clinical expression of infections by two tick-borne microorganisms. The latter, although regularly speculated, is not often reported. Hence, we conducted a systematic review on co-infections between B. burgdorferi s.l., the etiological agent of Lyme borreliosis, and other microorganisms potentially transmitted to humans by Ixodes spp. ticks. A total of 68 relevant articles were included, presenting 655 cases of possible co-infections. Most cases of co-infections corresponded to patients with one tick-borne disease and presenting antibody against another tick-borne microorganism. Co-disease was particularly frequent in two situations: patients with clinical symptoms of high fever and erythema migrans (EM), and patients with neurological symptoms linked to the TBEv or a neuroborreliosis. No impact on severity was evidenced. Further studies are needed to better appreciate the frequency and the impact of co-infections between several tick-borne microorganisms.

Blaschko-Linear Manifestations of Multifactorial Polygenic Diseases (BLMMPD) are rare. Their underlying pathogenesis is not known but genetic mosaicism is supposed to be involved. To describe a series of patients with BLMMPD and to establish a meaningful classification of these manifestations. We retrospectively retrieved the records of all the patients with Blaschko-linear lesions followed at our institution between 1994 and 2007. Only well-documented cases of BLMMPD were included. 17 cases were reviewed (11 men and 6 women, mean age 42 years), and the following diagnoses were established: psoriasis (4 cases), lupus erythematosus (1 case), lichen planus (4 cases), dermatomyositis (1 case), adult-onset lichen striatus (4 cases) and adult-onset blaschkitis (3 cases). Careful analysis allowed us to individualize 4 distinct nosological situations: in "type A" manifestations, patients had isolated Blaschko-linear lesions, either of a disease nosologically characterized in a non-segmental manner ("type Aα", e.g. Blaschko-linear psoriasis) or of a disease defined by its Blaschko-linearity ("type Aβ, e.g. lichen striatus); while in "type B" manifestations, patients had other signs of disease, i.e. either non-segmental skin lesions of the same type ("type Bα", e.g. Blaschko-linear psoriasis plus non Blaschko-linear psoriatic lesions), or distinct cutaneous or extra-cutaneous manifestations ("type Bβ", e.g. Blaschko-linear calcinosis cutis in a patient with otherwise typical dermatomyositis). We propose a comprehensive classification of BLMMPD in well distinct nosological situations, which should be of help if we wish to elucidate the pathogeny of those complex disorders.