Treatment of Miescher's cheilitis granulomatosa in Melkersson-Rosenthal syndrome.

Cheilitis granulomatosa is the most frequent dermatological sign in the Melkersson-Rosenthal syndrome. We reviewed 27 cases of this syndrome diagnosed and treated in the last 20 years. All the patients were surgically treated and received intralesional corticosteroids during surgery and tetracycline hydrochloride (500 mg, twice daily) after the operation to prevent recurrence.

Two ancient allelic lineages at the single classical class I locus in the Xenopus MHC.

Unlike all other vertebrates examined to date, there is only one detectable class I locus in the Xenopus MHC. On the bases of a nearly ubiquitous and high tissue expression, extensive polymorphism, and MHC linkage, this gene is of the classical or class Ia type. Sequencing analysis of class Ia cDNAs encoded by eight defined MHC haplotypes reveals two very old allelic lineages that perhaps emerged when humans and mice diverged from a common ancestor up to 100 million years ago. The unprecedented age of these lineages suggests that different class Ia genes from ancestors of the laboratory model Xenopus laevis are now expressed as alleles in this species. The lineages are best defined by their cytoplasmic and alpha2 peptide-binding domains, and there are highly diverse alleles (defined by the alpha1 peptide-binding domain) in each lineage. Surprisingly, the alpha3 domains are homogenized in both lineages, suggesting that interallelic gene conversion/recombination maintains the high sequence similarity.

Cytokine secretion of myelin basic protein reactive T cells in patients with multiple sclerosis.

The objective of this study was to determine whether autoreactive T cells in patients with multiple sclerosis (MS) are polarized and committed in their differentiation to a stable cytokine phenotype or whether the cytokine secretion can be altered. We examined the cytokines secreted by myelin basic protein (MBP) as compared to tetanus toxoid-reactive (TT) T cells in 12 patients with relapsing remitting MS (RR-MS), 9 patients with chronic progressive MS (CP-MS), and 14 normal individuals. A total of 5094 short term T cell lines to MBP and TT were generated in the presence of growth conditions promoting Th1 (IL-12/alpha-IL-4 mAb) or Th2 (IL-4/alpha-IL-12 mAb) cytokine secretion. Antigen-specific cytokine secretion from normals and MS patients could be shifted to a Th1 or Th2 type phenotype depending upon culture conditions, indicating that the phenotype of MBP reactive T cells can be altered even in longstanding chronic progressive MS. There were no significant differences in the cytokine patterns secreted by MBP reactive T cells in patients with MS as compared to normal individuals. However, CP-MS patients tended to have fewer MBP reactive T cells secreting IL-4 when cultured with IL-12/anti-IL-4 mAb and more IFN-gamma secreting MBP reactive T cells when cultured with IL-4/anti-IL-12 mAb as compared to both normal controls and RR-MS, suggesting that cells from these patients might be more polarized or that fewer undifferentiated MBP-reactive cells are present in these individuals. The most striking observation was that in contrast to the RR-MS patients and normal controls, almost none of the MBP reactive T cells secreting cytokines in CP-MS incorporated 3[H]thymidine. This may be due to chronic in vivo stimulation in the presence of IL-12, or because these T cells may have entered a terminally differentiated state. Nonetheless, the ability to alter the cytokine secretion of autoreactive T cell lines even in longstanding autoimmune disease indicates that cytokine therapy might have therapeutic benefits by switching the function of myelin reactive T cells such that they are non-pathogenic.

Expansion by self antigen is necessary for the induction of experimental autoimmune encephalomyelitis by T cells primed with a cross-reactive environmental antigen.

Cross-reactivity with environmental antigens has been postulated as a mechanism responsible for the induction of autoimmune disease. Experimental autoimmune encephalomyelitis is a T cell-mediated autoimmune disease model inducible in susceptible strains of laboratory animals by immunization with protein constituents of myelin. We used myelin proteolipid protein (PLP) peptide 139-151 and its analogues to define motifs to search a protein database for structural homologues of PLP139-151 and identified five peptides derived from microbial Ags that elicit immune responses that cross-react with this self peptide. Exposure of naive SJL mice to the cross-reactive environmental peptides alone was insufficient to induce autoimmune disease even when animals were treated with Ag-nonspecific stimuli (superantigen or LPS). However, immunization of SJL mice with suboptimal doses of PLP139-151 after priming with cross-reactive environmental peptides consistently induced experimental autoimmune encephalomyelitis. Furthermore, T cell lines from mice immunized with cross-reactive environmental peptides and restimulated in vitro with PLP139-151 could induce disease upon transfer into naive recipients. These data suggest that expansion by self Ag is required to break the threshold to autoimmune disease in animals primed with cross-reactive peptides.

Heteroclitic proliferative responses and changes in cytokine profile induced by altered peptides: implications for autoimmunity.

Productive engagement of T cell receptors (TCRs) by cognate ligand (major histocompatibility complex plus peptide) leads to proliferation, differentiation, and the elaboration of effector functions. Altered peptides generated by single amino acid substitutions in the antigenic peptide have diverse effects on the outcome of the T cell response. We have generated an altered peptide (Q144) from an autoantigenic peptide of myelin proteolipid protein 139-151 by a single amino acid substitution (from tryptophan to glutamine) in the primary TCR contact at position 144 that is capable of inducing CD4(+) T cell responses in H-2(s) mice. By using a Q144-specific T cell clone (Q1.1B6), we see a hierarchy in T cell proliferation and cytokine production with various position 144 substituted peptides and have identified a peptide (L144) that hyperstimulates this T cell clone. In contrast to Q144, L144 induces maximal proliferation at 7 logs lower antigen concentration, induces greater cell death at higher antigen dose, and induces the secretion of cytokines not detected following stimulation with the cognate ligand. This heteroclitic T cell response associated with changes in cytokine profile was observed with several other T cell clones of different specificities. The L144 peptide also induces costimulation independent proliferation and cytokine production from the Q1.1B6 T cell clone. We describe this as a superagonist response. Such responses may have a role in the initiation of autoimmunity by promoting a proinflammatory environment following ligation of a cross-reactive TCR on autoreactive T cells.

Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading.

Multiple sclerosis (MS) is a T cell-mediated autoimmune demyelinating disease, which may be initiated by a virus infection. Theiler's murine encephalomyelitis virus (TMEV), a natural mouse pathogen, is a picornavirus that induces a chronic, CD4+ T cell-mediated demyelinating disease with a clinical course and histopathology similar to that of chronic progressive MS (ref. 3). Demyelination in TMEV-infected mice is initiated by a mononuclear inflammatory response mediated by virus-specific CD4+ T cells targeting virus, which chronically persists in the CNS (ref. 4-6). We show that beginning 3-4 weeks after disease onset, T-cell responses to multiple myelin autoepitopes arise in an ordered progression and may play a pathologic role in chronic disease. Kinetic and functional studies show that T-cell responses to the immunodominant myelin proteolipid protein epitope (PLP139-151) did not arise because of cross-reactivity between TMEV and self epitopes (that is, molecular mimicry), but because of de novo priming of self-reactive T cells to sequestered autoantigens released secondary to virus-specific T cell-mediated demyelination (that is, epitope spreading). Epitope spreading is an important alternate mechanism to explain the etiology of virus-induced organ-specific autoimmune diseases.

Antinuclear antibodies in patients with lichen planus.

Lichen planus (LP) is a mucocutaneous syndrome of yet uncertain pathogenesis, and it has usually been considered to be a dermatosis without antinuclear antibodies (ANA) nor other specific auto-antibodies. Over 10 years ago a series of indirect immunofluorescence researches with patients' lesional skin and serum disclosed the presence of lichen planus specific antigens (LPSA). After this, a number of substrates have been submitted for evaluation. In this study we have carried out indirect immunofluorescent test in relation with different substrates, with the aim of verifying whether the negative results previously obtained were due to poor sensitivity of the substrates employed. Subsequently we have compared the results obtained in the erosive forms of LP with those obtained in the non-erosive forms. We have concluded that rat oesophagus is a better substrate for the detection of ANA in patients with LP, as it has proved to have a positivity rate of 40.42%. Monkey oesophagus has provided a rate of 27.6%, and HEP-2 cells and rat liver have proved to be unsuitable. In addition, we have observed that the frequency of ANA is higher in the erosive forms of LP (P = 0.0389). In this article we demonstrate that the presence of ANA in patients with LP depends on the substrate employed, the most suitable substrate being rat oesophagus. Also, we demonstrate that ANA is more frequently observed in patients with erosive LP.

IL-12 induces human T cells secreting IL-10 with IFN-gamma.

A clear differentiation of Th1 and Th2 cytokine-secreting subsets in humans has not yet been defined. To further examine cytokine-directed differentiation of human T cell responses to both exogenous and autoantigens, we generated 346 short term T cell lines at limiting dilutions from six normal individuals to tetanus toxoid and myelin basic protein in the presence of IL-2 with or without the addition of IL-12 and anti-IL-4 mAb. T cell lines were examined for [3H]thymidine incorporation and cytokine secretion of IFN-gamma, IL-4, and IL-10. After culture in the presence of IL-12 and anti-IL-4 mAb, the predominant T cell response to Ag stimulation was simultaneous secretion of IL-10 and IFN-gamma. The concomitant secretion of IL-10 and IFN-gamma by T cells was confirmed by stimulating lines in the absence of APCs with plate-bound anti-CD3 mAb after two rounds of Ag-specific stimulation. Moreover, IL-12 enhanced IL-10 and IFN-gamma production in a myelin basic protein-reactive T cell clone, demonstrating that a differentiated T cell clone could be induced to secrete both cytokines. The addition of a neutralizing anti-IFN-gamma Ab to cultures with IL-12 and anti-IL-4 mAb during the generation of tetanus toxoid-reactive lines had no effect on the induction of IL-10 and IFN-gamma secretion, indicating that IL-12 and not IFN-gamma was responsible for the induction of this subset of T cells. Thus, in human T cells, IL-12 induces concomitant secretion of IL-10 and IFN-gamma.

[Epidemiology of alcohol and drug abuse in Paraguay]. / Epidemiología del abuso del alcohol y las drogas en el Paraguay.

The results of a prevalence study on use- and abuse- of psychoactive substances, among a population aged 12 to 45 in Paraguay are presented. Presence of the depressive syndrome as well as attitudes and beliefs related to the use of psychoactive substances were also investigated. A bilingual questionnaire was drafted--i.e. a Spanish version and a Guarani version due to the Paraguayans' bilingual characteristic--that yielded acceptable validity and reliability levels. A stratified random sample was applied, with a total of 2,504 questionnaires filled out. Weighted data are shown here as studied by sex, age-group, socio-economic level, and presence of the depressive syndrome. Substance/alcohol use patterns were found out to be widely tolerant about abusing legal substances such as alcohol, tobacco, and psychotropic drugs. As regards illicit substances use, inhalants head the list followed by marijuana at a close range.

Epidemiología del abuso del alcohol y las drogas en el Paraguay. / [Epidemiology of alcohol and drug abuse in Paraguay]

The results of a prevalence study on use- and abuse- of psychoactive substances, among a population aged 12 to 45 in Paraguay are presented. Presence of the depressive syndrome as well as attitudes and beliefs related to the use of psychoactive substances were also investigated. A bilingual questionnaire was drafted--i.e. a Spanish version and a Guarani version due to the Paraguayans bilingual characteristic--that yielded acceptable validity and reliability levels. A stratified random sample was applied, with a total of 2,504 questionnaires filled out. Weighted data are shown here as studied by sex, age-group, socio-economic level, and presence of the depressive syndrome. Substance/alcohol use patterns were found out to be widely tolerant about abusing legal substances such as alcohol, tobacco, and psychotropic drugs. As regards illicit substances use, inhalants head the list followed by marijuana at a close range.

Epidemiología del abuso del alcohol y las drogas en el Paraguay. / [Epidemiology of alcohol and drug abuse in Paraguay]

The results of a prevalence study on use- and abuse- of psychoactive substances, among a population aged 12 to 45 in Paraguay are presented. Presence of the depressive syndrome as well as attitudes and beliefs related to the use of psychoactive substances were also investigated. A bilingual questionnaire was drafted--i.e. a Spanish version and a Guarani version due to the Paraguayans bilingual characteristic--that yielded acceptable validity and reliability levels. A stratified random sample was applied, with a total of 2,504 questionnaires filled out. Weighted data are shown here as studied by sex, age-group, socio-economic level, and presence of the depressive syndrome. Substance/alcohol use patterns were found out to be widely tolerant about abusing legal substances such as alcohol, tobacco, and psychotropic drugs. As regards illicit substances use, inhalants head the list followed by marijuana at a close range.