Pre- vs. post-pubertal onset of vitiligo: multivariate analysis indicates atopic diathesis association in pre-pubertal onset vitiligo.

BACKGROUND: Limited epidemiological data exist that compare clinical features of pre- and post-pubertal nonsegmental vitiligo. OBJECTIVES: To compare factors associated with pre- and post-pubertal onset vitiligo. PATIENTS AND METHODS: A prospective observational study was conducted of patients with vitiligo attending the clinic between 1 January 2006 and 1 July 2011. The Vitiligo European Task Force questionnaire was completed for each patient and thyroid function and antithyroid antibodies were screened. Other forms of vitiligo (segmental, focal, mucosal, not classifiable) were excluded. RESULTS: A total of 679 patients were included; 422 had post-pubertal and 257 pre-pubertal onset of vitiligo. Vitiligo universalis was seen only in post-pubertal onset. In univariate analysis, there was no significant statistical difference for sex, Koebner phenomenon or disease activity between both groups; thyroid disease or presence of thyroid antibodies was more frequent in post-pubertal onset [odds ratio (OR) 0·31, P < 0·003] whereas atopic dermatitis was more often associated with or preceding pre-pubertal onset (OR 2·42, P = 0·006). In multivariate analysis, halo naevi, family history of vitiligo, premature hair greying, atopic dermatitis and previous episode of spontaneous repigmentation were independently associated with pre-pubertal onset. In contrast, stress as onset factor, personal history of thyroid disease and acrofacial type were associated with post-pubertal onset. CONCLUSIONS: Pre-pubertal onset vitiligo is strongly associated with personal and family history of atopy, suggesting that the predisposing immune background in vitiligo is not limited to autoimmunity, as also noted in alopecia areata. This study also suggests reconsidering the epidemiological data on sex ratio in vitiligo.

Multivariate analysis of factors associated with early-onset segmental and nonsegmental vitiligo: a prospective observational study of 213 patients.

BACKGROUND: Although mixed forms have been described recently, segmental (SV) and nonsegmental vitiligo (NSV) are considered as clinically distinct. However, limited epidemiological data are available to help distinguish associated factors, and recent genome-wide association studies have been restricted to NSV. The higher prevalence of SV in children is helpful when comparing the two major presentations of the disease. OBJECTIVE: To compare factors associated with SV and NSV, especially for markers of autoimmunity or autoinflammation. METHODS: We conducted a single-centre prospective observational study in patients aged 17 years or under with a confirmed diagnosis of SV or NSV at the vitiligo clinic between 1 January 2006 and 1 July 2010. The Vitiligo European Task Force questionnaire was completed for each patient, and thyroid function and antithyroid antibodies were screened if not obtained in the previous year. Other forms of vitiligo (focal, mucosal, not classifiable) were excluded. RESULTS: A total of 213 children were included, 142 with NSV, 59 with SV and 12 with mixed vitiligo. There was no significant statistical difference for sex or age at onset between patients with SV and NSV. Halo naevi were significantly more frequent in NSV than in SV [odds ratio (OR) 7·58, P < 0·01). Patients with NSV more frequently had a positive family history of vitiligo (OR 2·25, P=0·02) and a marked familial autoimmunity background (OR 2·22, P = 0·01). CONCLUSIONS: Our study clearly shows that features of inflammation (pruritus)/autoimmunity (halo naevi, thyroid antibodies) are strongly linked to NSV, together with a familial background of vitiligo and autoimmunity.

Mechanism of extracellular thiol nitrosylation by N(2)O(3) produced by activated macrophages.

Reactive nitrogen intermediates are synthesized by activated macrophages. These molecules, and nitrous anhydride (N(2)O(3)) in particular, are known to be potent nitrosylating species. We investigated the role of macrophage-derived N(2)O(3) in extracellular nitrosylation. We used dilution experiments to demonstrate the intracellular production of N(2)O(3) and its export into the extracellular medium, with a rate constant k(ex) = 6.8 x 10(6) M s(-1). The kinetics of the competition between extracellular hydrolysis of N(2)O(3) and its reaction with added glutathione were also studied. We obtained a value of the rate constant k(GSH) for the latter reaction of 4.4 x 10(7) M(-1) s(-1), consistent with earlier determinations in cell-free systems. The implications of these results in human albumin nitrosylation were investigated. Nitrosylated albumin was detected in activated macrophages supernatants using an anti-NO-acetylated cysteine antibody. It was estimated that 10% of N(2)O(3) produced by activated cells participate in extracellular nitrosylation. N(2)O(3) thus appears to be a new effector molecule of the immune system, as an agent for the nitrosylation of albumin, the main nitric oxide carrier in vivo.

Triggering of CD23b antigen by anti-CD23 monoclonal antibodies induces interleukin-10 production by human macrophages.

The aim of this study was to evaluate the capacity of human macrophages to produce interleukin (IL)-10 upon stimulation of membrane CD23. An anti-CD23 monoclonal antibody (mAb) was found to elicit the expression of the specific mRNA for IL-10 in CD23-bearing macrophages, and to induce a time-dependent production of this cytokine with a maximal effect reached after 12 h. Inasmuch as we previously reported that CD23 ligation evoked the generation of nitric oxide and of cAMP, the effect of the Rp diastereoisomer of adenosine 3', 5'-cyclic phosphorothioate (Rp-cAMP, an inhibitor of the cAMP pathway) and of NG-monomethyl-L-arginine (L-NMMA, an inhibitor of the nitric oxide pathway) were evaluated on CD23-induced IL-10 production. In the presence of Rp-cAMP, the CD23-induced production of IL-10 and of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) was totally abrogated, whereas, in the presence of L-NMMA, IL-10 production was enhanced and TNF-alpha production was suppressed. In addition, neutralization of IL-10 with an anti-IL-10 mAb increased both the magnitude and duration of CD23-driven TNF-alpha production. Such an inducing effect was observed with different anti-CD23 mAb (clone 135, MHM6 and 25), indicating that the triggering of the CD23 molecule at the surface of human macrophages induced the generation of IL-10 through a cAMP-dependent mechanism. Concomitantly this generation of IL-10 was down-regulated by nitric oxide, which was also produced after triggering of the CD23 antigen. Taken together these data indicated that human macrophages produced IL-10 after triggering of the CD23 molecule and that this production could regulate the inflammatory state of these cells.

Canine visceral leishmaniasis: successful chemotherapy induces macrophage antileishmanial activity via the L-arginine nitric oxide pathway.

Following successful chemotherapy in canine visceral leishmaniasis, monocyte-derived macrophages can induce antileishmanial activity via a gamma interferon-dependent mechanism in the presence of autologous lymphocytes. The killing of leishmania correlated with the induction of the NO synthase pathway, because it correlated with the generation of nitrogen derivative production and was abrogated in the presence of NG-monomethyl-L-arginine, a competitive inhibitor of the NO synthase pathway. The level of L-citrulline in serum, which was produced after activation of the NO synthase pathway, was markedly enhanced in dogs receiving successful chemotherapy. Taken together, these data indicate that following successful chemotherapy of visceral leishmaniasis, leishmania parasites are killed by macrophages activated by gamma interferon-producing lymphocytes via an NO-dependent mechanism.

Evidence for a role of Fc epsilon RII/CD23 in the IL-4-induced nitric oxide production by normal human mononuclear phagocytes.

IL-4 stimulates NO production by human monocytes. After 6 days of culture with IL-4, human monocytes released detectable amounts of nitrite and L-citrulline that were inhibited in the presence of nitro-L-arginine (1 mM). Incubation with an anti-CD23 mAb Fab fragment that suppressed the biological effect of CD23 led to a strong reduction (50 to 70%) of the IL-4-induced nitrite and L-citrulline production. Ligation of membrane-associated CD23 or stimulation with recombinant soluble CD23 elicited monocytes to release nitrite and L-citrulline that was suppressed by nitro-L-arginine. Preactivation of human monocytes with IFN-gamma led to subsequent increased IL-4- and CD23-driven nitrite and L-citrulline productions that were also suppressed in the presence of either nitro-L-arginine or the anti-CD23 mAb Fab fragment. The CD23 molecule under its membrane or soluble form thus regulates NO generation by human monocytes. In addition, the IL-4-induced NO production could be mediated, at least in part, by CD23.

Ligation of CD23 activates soluble guanylate cyclase in human monocytes via an L-arginine-dependent mechanism.

Transduction through Fc epsilon R2/CD23 was analyzed in normal human monocytes using immunoglobulin E (IgE)-anti-IgE immune complexes (IgE ICs) and monoclonal antibodies (mAbs) to CD23. Anti-CD23 mAb and IgE IC triggered a time-dependent increase in cGMP and cAMP in interleukin-4-preincubated (CD23+) but not in unstimulated (CD23-) monocytes. Maximal cGMP and cAMP accumulations were observed 10 and 20 min, respectively, after the onset of CD23 ligation. The increase in cGMP was inhibited with N omega-monomethyl-L-arginine (L-NMMA), which also partially affected cAMP accumulation. Addition of an anti-CD23 mAb Fab fragment inhibited the IgE IC- and the anti-CD23 mAb-induced cGMP and cAMP accumulation, confirming the engagement of CD23. In addition, IgE IC and anti-CD23 mAb induced, at least in some donors, a production of nitrite that was inhibited in the presence of L-NMMA. Taken together, these findings suggest a possible involvement of the nitric oxide synthase pathway in IgE IC-mediated activation of CD23+ monocytes.

[Physiopathological role of low affinity IgE receptor (CD23) in hematopoietic cells]. / Rôle physiopathologique du récepteur de basse affinité des IgE (CD23) dans les cellules hématopoïétiques.

Ligation of the low affinity IgE receptor by specific monoclonal antibodies or multivalent IgE complexes result in the transduction of signals which differ according to the CD23 isotype expressed by the various cell types. In B lymphocytes, it elicits the early activation of phospholipase C through a mechanism involving a G-protein insensitive to Pertussis toxin, followed by a late phase of cAMP accumulation. In monocytes, which express the CD23b isoform, ligation of CD23 was also found to induce a delayed accumulation of cAMP, that was largely dependent on a prior cGMP increase through a mechanism involving the activation of a NO synthase. This pathway, which appears to be exacerbated in allergic diseases, seems to play an important role in the differentiation of cells of the monocytic lineage, their capacity to release proinflammatory mediators and their cytotoxic functions.

Biochemical and functional alterations induced by CD23 ligation in the human promonocytic cell line U937.

The early events triggered in interleukin-4 (IL-4)-stimulated U937 cells by ligation of CD23/Fc epsilon RII with specific monoclonal antibodies (mAb) were analysed, as a model of the action of this molecule on the differentiation of promonocytic cells. As well as IL-4-activated human monocytes, addition of anti-CD23 mAb to IL-4-treated U937 cells triggered cAMP accumulation but did not evoke significant polyphosphoinositide hydrolysis. However, by a microspectrofluorometric technique allowing single cell analysis, anti-CD23 mAb was found to elicit calcium mobilization in these cells. In addition, the treatment induced phenotypic alterations in these cells, as evidenced by the acquisition of the monocyte marker CD14 and the increase of the alpha-chain (CD11a) and of the common beta-chain (CD18) of the leucocyte function-associated antigen 1 (LFA-1) family antigens. Although weaker than in monocytes, CD23 ligation evoked a small secretion of the pro-inflammatory mediators IL-6 and thromboxane B2. These data suggest that a significant maturation of promonocytic cells towards a more mature monocytic phenotype can be achieved through successive exposure to IL-4 and CD23 ligation.

Effect of CD23 on purified human hematopoietic cells.

We report herein the effect of soluble CD23 (sCD23) on the differentiation of lymphoid and myeloid precursors. CD23 is known as the low affinity receptor for IgE. In addition to it, our results indicate that sCD23 in synergy with IL1 is able to promote the maturation of normal and leukemic hematopoietic progenitor cells.

The differentiation of human pro-thymocytes along the TCR-alpha/beta pathway in vitro is accompanied by the site-specific deletion of the TCR-delta locus.

The nested location of the TCR-delta gene within the TCR-alpha locus is a common feature of both mouse and human. Yet alpha/beta and gamma/delta T cells represent two separate lineages. We have previously proposed that a specific rearrangement event (delta Rec--psi J alpha) resulting in the specific deletion of the TCR-delta gene could be responsible for the independent usage of these two loci. We used an in vitro model of T cell differentiation to test this hypothesis. We show that in culture conditions (IL-1 + sCD23) which promote the development of alpha/beta expressing T cells exclusively, the specific deletion of the TCR-delta locus occurs very rapidly, probably before the productive rearrangement of the TCR-alpha gene. These results clearly demonstrate that the specific deletion of the TCR-delta gene could be the initial regulatory event that imprints the irreversible commitment of T cell differentiation along the alpha/beta pathway.

Origin of malignant centrofacial granulomas: surface markers and gene rearrangement of malignant cells.

Malignant centrofacial granuloma (MCFG) is a clinical entity characterized by a relentless ulceration of the upper airway involving the nose, palate, and face, without any demonstrable etiology. The origin of 11 cases were analyzed with the help of cell-surface immunostaining in all and with T-cell receptor gene (TCR) rearrangement in 3. The results show that most of the cases of MCFG are in fact T-cell lymphomas with cell-surface antigens (CD2, CD7, CD3) consistent with either early or mature T lymphocytes. However, some cases exhibit B-lymphoid (CD19, CD20) or histiomonocytic (CD13, CD14) lineage-specific markers. In conclusion, despite its remarkable clinical unity, MCFG is a heterogeneous group of neoplastic diseases, most but not all of which may be classified as T-cell lymphoma.

[Contribution of immunologic technics to the characterization of lethal midline granuloma of unknown origin]. / Apport des techniques immunologiques au démembrement des granulomes malins centro-faciaux de cause inconnue.

The lethal midline granuloma is a clinical entity characterized by a relentless ulceration of the upper airway involving the nose, the palate and the face, without any demonstrable etiology. We have applied the cell membrane immunostaining techniques to twelve cases. According to the results, it seems that most of the cases are in fact T-cell lymphomas with membrane staining consistent with either precursor or mature lymphoid T-cells. Some cases, however, exhibit an immunostaining pattern compatible with other origins, the proliferating cells belonging either to the B lymphoid or to the histio-monocytic lineages. We conclude that the lethal midline granuloma is an heterogeneous group of neoplastic diseases, in the most part close to a T cell lymphoma, but with a remarkable clinical unity.