Cortisol and proinflammatory cytokine profiles in type 1 (reversal) reactions of leprosy.

PURPOSE: Cortisol levels in the circulation and at the sites of peripheral inflammation regulate type 1 (Reversal) reactions in leprosy akin to delayed type hypersensitivity reactions (DTH). In this study we determine the extent to which the differential mRNA expression of genes encoding cortisone-cortisol shuttle enzymes (11 ß hydroxysteriod dehydrogenase I & II (11 ß HSD I & II)), circulatory levels of proinflammatory cytokines (IL-6, IL-7, IP-10, IL-17F, IL-23, TNF-α, IL-1ß, PDGF BB and CRP) and cortisol are associated with development of type 1 reactions in leprosy. METHODS: Urine, blood and incisional skin biopsy samples from site of lesions were collected from 49 newly diagnosed untreated leprosy cases in T1R and 51 cases not in reaction (NR). mRNA expression levels of genes encoding 11 ß HSD I & II in skin biopsy samples were determined by realtime PCR. Cortisol levels from the lesional skin biopsies, serum and urine samples and serum proinflammatory cytokine levels were measured using ELISA. RESULTS: The mean expression ratios of 11 ß HSD I & II are significantly lower in leprosy cases with T1R when compared to the NR leprosy cases. Cortisol levels in lesional skin biopsies and in urine are significantly lower (p=0.001) in leprosy cases with T1R. Serum cytokine levels of IP-10, IL-17F, IL-IL-6 and TNF-α are significantly higher (p<0.05) in leprosy cases with T1R when compared the NR leprosy cases. CONCLUSION: Our study indicated an association of urinary and lesional skin cortisol levels with the manifestation of T1R in leprosy. IP-10, IL-17F, IL-6 and TNF-α can be potential prognostic serological markers and gene expression markers for early detection of type 1 reactions in leprosy.

Immediate hypersensitivity to rifampicin in 3 patients: diagnostic procedures and induction of clinical tolerance.

BACKGROUND: Desensitization with drugs may be indicated in some clinical situations. Apart from large experiences with beta-lactam antibiotics and cotrimoxazole in HIV infection, experience with other drugs is limited. Rifampicin may elicit exanthema and urticaria, and their pathomechanisms are not known in detail. Since therapy with rifampicin may be indispensable in mycobacterial infections or against multiresistant Staphylococcus aureus, desensitization may be indicated in some patients. OBJECTIVE: Report of immediate hypersensitivity to rifampicin and description of diagnostic and desensitization procedures. METHODS: We report 3 patients with immediate urticarial reactions to rifampicin. Diagnostic procedures included skin and in vitro tests (specific IgE, lymphocyte transformation test, LTT, and CAST). The non-irritant cutoff concentration was evaluated in 24 volunteers. A 7-day desensitization procedure was used. RESULTS: Only intradermal tests at a dilution of at least 1:10,000 (concentration of rifampicin approximately 0.006 mg/ml) were true positive, whereas in vitro tests (IgE, LTT and CAST) did not correctly identify hypersensitive patients. Two patients had positive accidental reexposure. All patients were successfully desensitized with rifampicin according to a slow 7-day protocol. CONCLUSIONS: Rifampicin rarely elicits immediate hypersensitivity symptoms which may be diagnosed by intradermal skin tests. In vitro tests did not contribute to the diagnosis. Therefore, an IgE-mediated mechanism remains to be proven. Desensitization with rifampicin using different protocols has been reported. In our 3 cases, clinical tolerance to rifampicin was achieved using a 7-day protocol.

Antigenic trigger for type 1 reaction in leprosy.

Type 1 (reversal or upgrading) reactions occur during or after chemotherapy in around 10% leprosy patients [Int J Lepr Other Mycobact Dis 61 (1993) 8-15]. The cause of this immunological upgrading is incompletely defined, although the approximately 2-fold increased risk of reaction in patients vaccinated with Mycobacterium w suggests that infection by mycobacteria other than Mycobacterium leprae may trigger this phenomenon [Vaccine 13 (1995) 1102-1110]. We report a case of borderline lepromatous leprosy in which we studied the antigenic specificity of peripheral blood mononuclear cells immediately before, and then during, a Type 1 reaction which provides more direct evidence in favor of this hypothesis.

Differential representations of memory T cell subsets are characteristic of polarized immunity in leprosy and atopic diseases.

We identified functionally polarized subsets of CD4 memory T cells on the basis of the expression of CD11a, CD45RA and CD62L. Within the several phenotypically distinct subsets of CD4 memory cells are two that, upon stimulation, produce primarily IL-4 (MT(2), CD45RA(-)CD62L(+)CD11a(dim)) or primarily IFN-gamma (MT(1), CD45RA(-)CD62L(-)CD11a(bright)). In addition, four other phenotypically distinct subsets of CD4 cells have unique cytokine profiles. To determine the clinical relevance of the representation of these cell types, we analyzed blood from patients with the chronic diseases leprosy and atopy. These diseases are characterized as immunologically polarized, since T cell responses in affected individuals are often strongly biased towards T(h)1 (dominated by IFN-gamma production) or T(h)2 (IL-4 production). We show here that this polarization reflects homeostatic or differentiation mechanisms affecting the representation of the functionally distinct subsets of memory CD4 T cells, MT(1) and MT(2). Significantly, the representation of the MT(1) and MT(2) subsets differs dramatically between subjects with tuberculoid leprosy (a T(h)1 disease), or lepromatous leprosy or atopic disease (T(h)2 diseases). However, there was no difference in the cytokine profiles of these or any of the other finely resolved CD4 subsets, when compared between individuals across all disease states. Thus, it is the representation of these subsets in peripheral blood that is diagnostic of the polarized state of the immune system.

Zinc-controlled Th1/Th2 switch significantly determines development of diseases.

Functional, excessive-possibly temporary-deficiencies of the trace element zinc can change immune functions prematurely from predominantly cellular Th1 responses to humoral Th2 responses. T helper (Th1) cells produce cytokines such as interleukin-2 (IL-2) and interferon gamma, thereby controlling viral infections and other intracellular pathogens more effectively than Th2 responses through cytokines such as IL-4, IL-5, IL-6 and IL-10. The accelerated shift from the production of extra Th1 cells during these cellular immune activities to more Th2 cells with their predominantly humoral immune functions, caused by such a zinc deficiency, adversely influences the course of diseases such as leprosy, schistosomiasis, leishmaniasis and AIDS, and can result in allergies. It is noteworthy that AIDS viruses (HIVs) do not replicate in Th1 cells, which probably contain more zinc, but preferentially in the Th0 and Th2 cells; all the more so, because zinc and copper ions are known to inhibit intracellular HIV replication. Considering the above Th1/Th2 switch, real prospects seem to be offered of vaccination against such parasites as Leishmania and against HIVs.

Atopy and IgE in patients with leprosy.

The atopic status of patients with leprosy was assessed by medical history, physical examination, serum total IgE, and specific IgE antibodies to common allergens (by skin testing and RAST). Tests for specific IgE antibody to Mycobacterium leprae were performed by RAST and immunoblotting technique. We studied 28 patients with leprosy and 49 control subjects. The two groups did not differ significantly in the prevalence of atopic disease. The IgE level was significantly higher in the patients, however, than in the control subjects, whether there was atopy (296.1 versus 96.3 IU/ml) or not atopy (72.9 versus 18.9 IU/ml). Neither RAST nor immunoblotting technique detected significant levels of IgE antibodies to M. leprae. Our data indicate that leprosy was associated with increased total IgE level, but clinical atopy in patients with leprosy was similar to that in control subjects. The observed IgE increase in patients with leprosy appears to be generally nonspecific.