Management of patients with severe asthma: results from a survey among allergists and clinical immunologists of the Central Italy Inter-Regional Section of SIAAIC.

BACKGROUND: Asthma, and severe asthma in particular, is often managed within a specialized field with allergists and clinical immunologists playing a leading role. In this respect, the National Scientific Society SIAAIC (Società Italiana di Allergologia, Asma ed Immunologia Clinica), structured in Regional and Inter-Regional sections, interviewed a large number of specialists involved in the management of this respiratory disease. METHODS: A survey entitled "Management of patients with asthma and severe asthma" based on 17 questions was conducted through the SIAAIC newsletter in 2019 thanks to the collaboration between GlaxoSmithKline S.p.A. and the Inter-Regional Section of SIAAIC of Central Italy. RESULTS: Fifty-nine allergists and clinical immunologists participated to the survey, and 40 of them completed the entire questionnaire. Almost all of the specialists (88%) reported that asthma control was achieved in above 50% of their patients, even if only one third (32%) actually used validated clinical tools such as asthma control test (ACT). Poor adherence to inhaled therapy was recognized as the main cause of asthma control failure by 60% of respondents, and 2-5 min on average is dedicated to the patient inhaler technique training by two-thirds of the experts (65%). Maintenance and as-needed therapy (SMART/MART) is considered an appropriate approach in only a minority of the patients (25%) by one half of the respondents (52%). A high number of exacerbations despite the maximum inhalation therapy were recognized as highly suspicious of severe asthma. Patients eligible for biological therapies are 3-5% of the patients, and almost all the responders (95%) agreed that patients affected by severe asthma need to be managed in specialized centers with dedicated settings. Biological drugs are generally prescribed after 3-6 months from the initial access to the center, and once started, the follow-up is initially programmed monthly, and then every 3-6 months after the first year of treatment (96% of responders). After phenotyping and severity assessment, comorbidities (urticaria, chronic rhinosinusitis with or without nasal polyps, vasculitis, etc.) are the drivers of choice among the different biological drugs. In the management of severe asthma, general practitioners (GPs) should play a central role in selecting patients and referring them to specialized centers while Scientific Societies should train GPs to appropriately recognize difficult asthma and promote public disease awareness campaigns. CONCLUSIONS: This survey which collects the point of view of allergists and clinical immunologists from Central Italy highlights that asthma control is still not measured with validated instruments. There is a general consensus that severe asthma should be managed only in dedicated centers and to this aim it is essential to encourage patient selection from a primary care setting and develop disease awareness campaigns for patients.

Migrants and allergy: a new view of the atopic march.

Summary: Atopy is the result of the influence of environmental factors on genetically predisposed individuals. Migration flows represent an interesting model to study the possible reciprocal roles of genes and environment. In this review the following issues influencing the development of allergic sensitization and/or atopic disorders in migrants will be rooted out: 1) ethnicity, genetic polymorphisms and risk of atopy; 2) double faceted effects of parasitic infestations; 3) biodiversity loss and industrial progress. Moreover, an extensive revision of the literature about the relationship between the migratory status and allergy development is provided.

Identification of T-cell epitopes from benzylpenicillin conjugated to human serum albumin and implication in penicillin allergy.

BACKGROUND: There is in vitro evidence that T cells from allergic patients react to benzylpenicillin-human serum albumin (BP-HSA) bioconjugates. Our group has recently shown the existence of naïve CD4+ T cells recognizing BP-HSA in healthy donors. However, BP-haptenated peptides from HSA participating in the immunization of allergic patients have never been identified. The purpose of the present study is to identify immunodominant BP-haptenated peptides from HSA involved in immunization of patients to BP and to refine the frequency calculation of naïve CD4+ T cells recognizing BP. METHODS: Co-cultures were established with CD4+ T cells from non-allergic donors and mature autologous dendritic cells (DCs) loaded with BP-HSA or BP-haptenated peptides from HSA. The CD4+ T-cell response specific for BP-HSA or for individual BP-haptenated peptides was measured using an interferon-γ (IFN-γ) ELISpot assay. The frequency of BP-specific CD4+ T cells was then calculated using the Poisson distribution. BP-HSA and BP-haptenated peptides recognition by allergic patients was evaluated on peripheral blood mononuclear cells (PBMCs) using a lymphocyte transformation test (LTT). RESULTS: Results showed that BP-HSA and BP-haptenated peptides were recognized by naïve T cells from 15/16 and 13/14 tested healthy donors, respectively. Most donors responded to 3 peptides with BP covalently bound on lysines 159, 212, and 525. Two of these benzylpenicilloylated peptides (lysines 159 and 525) were also found to induce PBMCs proliferation in patients with allergic reaction to penicillins. CONCLUSION: This study identifies and characterizes for the first time the BP-haptenated peptides from HSA involved in the immunization of patients to penicillins.

Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells.

The effects exerted on the in vitro development of antigen-specific T cell lines and T cell clones by addition or neutralization of interleukin 12 (IL-12) in lymphocyte bulk culture were examined. T cell lines specific for Dermatophagoides pteronyssinus group I (Der p I) derived in the presence of IL-12 exhibited reduced ability to produce IL-4 and increased ability to produce interferon gamma (IFN-gamma), and developed into Der p I-specific CD4+ T cell clones showing a T helper type 0 (Th0)- or Th1-, instead of Th2-, like cytokine profile. In contrast, purified protein derivative (PPD)-specific T cell lines derived in the presence of anti-IL-12 antibody exhibited an increased ability to produce IL-4 and developed into PPD-specific CD4+ T cell clones showing a Th0-, instead of Th1-, like profile. The influence of IL-12 on the cytokine secretion profile of Der p I-specific T cell lines was not prevented by addition to lymphocyte bulk cultures of anti-IFN-gamma antibody, but could be at least partially inhibited by the removal from bulk cultures of CD16+ cells. Thus, IL-12 and CD16+ cells appear to have inhibitory effects on the development of IL-4-producing cells and to play an inductive role in promoting Th1-like responses.

Th2-like CD8+ T cells showing B cell helper function and reduced cytolytic activity in human immunodeficiency virus type 1 infection.

We analyzed at clonal level the functional profile of circulating or skin-infiltrating T lymphocytes from two individuals infected with the human immunodeficiency virus type 1 (HIV-1), suffering from a Job's-like syndrome (eczematous dermatitis, recurrent skin and sinopulmonary infections, and hypergammaglobulinemia E) and showing virtually no circulating CD4+ T cells. Most of the CD3+ T cell clones generated from both patients were CD4- CD8+ TCR alpha beta +. The others were CD4- CD8- TCR alpha beta + which exhibited reduced mRNA expression for the CD8 molecule or no mRNA expression for either CD4 or CD8 molecules. The great majority of both CD4- CD8+ and CD4- CD8- did not produce interferon (IFN) gamma and exhibited reduced cytolytic activity. Rather, most of them produced large amounts of both interleukin (IL) 4 and IL-5 and provided B cell helper function for IgE synthesis. These data suggest that a switch of cytolytic CD8+ T cells showing a Th1-like cytokine secretion profile to cells that make Th2-type cytokines, exhibit reduced cytolytic potential, and provide B cell helper function can occur in the course of HIV-1 infection. These cells may contribute to the reduced defense against viral infections and intracellular parasites and account for the elevated IgE serum levels, eosinophilia, and the allergic-like clinical manifestations seen in a proportion of HIV-1-infected individuals.

CD30 expression by CD8+ T cells producing type 2 helper cytokines. Evidence for large numbers of CD8+CD30+ T cell clones in human immunodeficiency virus infection.

A large panel of CD8+ T cell clones generated from peripheral blood lymphocytes (PBL) of healthy donors or human immunodeficiency virus (HIV)-infected individuals were assessed for both cytokine secretion profile and CD30 expression and release. The great majority of CD8+ T cell clones generated from healthy individuals showed the ability to produce interferon gamma (IFN-gamma), but not interleukin 4 (IL-4), and none of them either expressed membrane CD30 or released substantial amounts of soluble CD30 (sCD30) in their supernatant. In contrast, high numbers of CD8+ T cell clones generated from HIV-infected individuals, which produced IL-4 (and IL-5) in addition to IFN-gamma or IL-4 (and IL-5) alone, expressed membrane CD30 and released detectable amounts of sCD30 in their supernatants. Indeed, CD30 expression appeared to be positively correlated with the ability of CD8+ T cell clones to produce IL-4 and IL-5 and inversely correlated with their ability to produce IFN-gamma, whereas no correlation between CD30 expression and production of IL-10 was observed. These data suggest that CD30 is a marker for CD8+ T cells that have switched to the production of type 2 helper cytokines.

Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones.

Interleukin 12 (IL-12) facilitates the generation of a T helper type 1 (Th1) response, with high interferon gamma (IFN-gamma) production, while inhibiting the generation of IL-4-producing Th2 cells in polyclonal cultures of both human and murine T cells and in vivo in the mouse. In this study, we analyzed the effect of IL-12, present during cloning of human T cells, on the cytokine profile of the clones. The culture system used allows growth of clones from virtually every T cell, and thus excludes the possibility that selection of precommitted Th cell precursors plays a role in determining characteristics of the clones. IL-12 present during the cloning procedures endowed both CD4+ and CD8+ clones with the ability to produce IFN-gamma at levels severalfold higher than those observed in clones generated in the absence of IL-12. This priming was stable because the high levels of IFN-gamma production were maintained when the clones were cultured in the absence of IL-12 for 11 d. The CD4+ and some of the CD8+ clones produced variable amounts of IL-4. Unlike IFN-gamma, IL-4 production was not significantly different in clones generated in the presence or absence of IL-12. These data suggest that IL-12 primes the clone progenitors, inducing their differentiation to high IFN-gamma-producing clones. The suppression of IL-4-producing cells observed in polyclonally generated T cells in vivo and in vitro in the presence of IL-12 is not observed in this clonal model, suggesting that the suppression depends more on positive selection of non-IL-4-producing cells than on differentiation of individual clones. However, antigen-specific established Th2 clones that were unable to produce IFN-gamma with any other inducer did produce IFN-gamma at low but significant levels when stimulated with IL-12 in combination with specific antigen or insoluble anti-CD3 antibodies. This induction of IFN-gamma gene expression was transient, because culture of the established clones with IL-12 for up to 1 wk did not convert them into IFN-gamma producers when stimulated in the absence of IL-12. These results suggest that Th clones respond to IL-12 treatment either with a stable priming for IFN-gamma production or with only a transient low level expression of the IFN-gamma gene, depending on their stage of differentiation.

Anti-infliximab IgE and non-IgE antibodies and induction of infusion-related severe anaphylactic reactions.

BACKGROUND: Infliximab is a chimeric monoclonal antibody against TNF-alpha useful in the treatment of many chronic inflammatory diseases. Severe anaphylaxis has been reported during therapy, although the exact mechanism has not been fully defined. The reactions have been related to the infliximab immunogenicity and development of specific antibodies. AIMS OF THE STUDY: Evaluation of the development of IgE and non-IgE antibodies to infliximab and their relationship with infusion reaction. METHODS: Seventy-one patients (11 reactives, 11 therapeutically nonresponders, and 49 unreactive therapeutically responders) and 20 non-infliximab-exposed control subjects (ten rheumatoid arthritis, five spondyloarthropathies, five vasculitis) were evaluated for the presence of IgE (ImmunoCAP assay), IgM, and non-isotype-specific (ELISA assays) anti-infliximab antibodies. Sera were obtained at baseline and during the course of treatment, before each infliximab infusion. RESULTS: Eleven out of 71 patients had a hypersensitivity reaction to infliximab. Non-isotype-specific anti-infliximab antibodies were detected in eight reactive and two nonresponder patients. Three patients with severe reactions displayed anti-infliximab IgE antibodies and positive skin testing. Detectable levels of anti-infliximab IgM antibodies were shown in three additional IgE- and skin testing-negative patients. IgE and IgM antibodies to infliximab were not detectable in the two nonresponder patients. Antibodies developed before the 2nd and the 3rd infusion, and their appearance was strictly related to the timing of the reaction. CONCLUSIONS: This report indicates that in some patients with infliximab-related severe reactions, IgE or IgM antibodies against infliximab were detectable. The majority of reactions could be predicted by the appearance of anti-infliximab antibodies.

Influence of total serum IgE levels on the in vitro detection of beta-lactams-specific IgE antibodies.

BACKGROUND: Allergic reactions to beta-lactams are a frequent cause of adverse drug reactions; the diagnosis is based on history, clinical examination, skin testing (prick and intradermal) and demonstration of serum-specific IgE antibodies (Abs). OBJECTIVE: We compared the diagnostic performance of the Phadia CAP system for the detection of IgE to beta-lactams carried out using the new test with cut-off limits of 0.10 kUA/L and the old test with cut-off limits of 0.35 kUA/L for positive results; subsequently, we analysed the effect of total serum IgE values and of atopic phenotype on the diagnostic performance of the tests. METHODS: The study comprised a total of 34 patients with a history of immediate adverse reactions to beta-lactams, which were confirmed by positive skin testing, and 115 control subjects with tolerance to beta-lactams over the last year. The Phadia CAP System was used for the determination of serum total and specific IgE Abs towards penicilloyl G (c1), penicilloyl V (c2), ampicilloyl (c5) and amoxicilloyl (c6). The overall diagnostic performance was assessed as a diagnostic odds ratio (DOR). RESULTS: The new test showed a higher sensitivity (85% vs. 44%) than the old test and a lower specificity (54% vs. 80%) but the overall diagnostic performance was poor (DOR 6.78 vs. 3.16, P = 0.333) in both tests. The total IgE value influences the DOR of both tests; DOR was better for values under 200 kU/L [DOR = 66; 95% confidence interval (CI): 11.3-384.1] or 500 kU/L (DOR = 45.7; 95% CI: 5.3-394.4) for the new and old tests, respectively. CONCLUSIONS: The reduction in the positive cut off value has not significantly improved the overall diagnostic performance of the beta-lactams-specific IgE assay. Because of the influence of serum total IgE on the detection of beta-lactam-specific IgE Abs, the combination of both tests is mandatory in the in vitro diagnostic approach of beta-lactam allergy.

Safety and tolerability of infliximab therapy: suggestions and criticisms based on wide clinical experience.

Infliximab, an IgG1 monoclonal chimeric antibody against tumor necrosis factor (TNF)-alpha, represents the main biological drug employed for the treatment of several immuno-mediated inflammatory disorders. Infliximab infusion can be complicated by clinically heterogeneous adverse reactions, potentially interfering with the course of treatment. We analysed the adverse events recorded in 49 patients affected by different chronic inflammatory disorders (rheumatoid arthritis, seronegative spondyloarthritis, Behçet's disease, Wegener's granulomatosis, Churg-Strauss syndrome, Cogan's disease) who were receiving a total of 709 infliximab infusions, in order to correlate the development of infliximab reactions and their features to some potential risk factors. We displayed a lower frequency of infusion reactions (1.5 percent; 11 out of 709 infusions) than those previously reported. However, patients suffering from rheumatoid arthritis and/or patients who underwent re-treatment after a long period, showed a higher prevalence of infliximab-related reactions. In conclusion, in our experience infliximab treatment is rarely complicated by adverse reactions which are, more importantly, almost always mild. Some good clinical practices, such as the low rate of infusion, pre-treatment with anti-histamine and prednisone in all patients, chronic immunosuppressive therapy and avoidance of long intervals between infusions may represent a combined useful strategy to reduce the frequency of infliximab reactions and to increase safety.

Defective in vitro production of gamma-interferon and tumor necrosis factor-alpha by circulating T cells from patients with the hyper-immunoglobulin E syndrome.

Circulating T cells from four patients with the hyper-IgE syndrome were found to produce significantly lower concentrations of interferon-gamma (IFN-gamma) in response to stimulation with phytohemagglutinin (PHA) than did T cells from eight age-matched healthy controls, three patients with atopic dermatitis and one patient with chronic granulomatous disease. A clonal analysis revealed that patients with hyper-IgE syndrome had markedly lower proportions of circulating T cells able to produce IFN-gamma and tumor necrosis factor-alpha (TNF-alpha) in comparison with controls. In contrast, the proportions of peripheral blood T cells able to produce IL-4 or IL-2 were not significantly different in patients and controls. All the four patients with hyper-IgE syndrome showed high proportions of circulating CD4+ helper T cells able to induce IgE synthesis in allogeneic B cells, as well. Such an activity for IgE synthesis appeared to be positively correlated with IL-4 production by T cells and inversely related to the ability of the same T cells to produce IFN-gamma. Since IFN-gamma exerts an inhibitory effect on the synthesis of IgE and both IFN-gamma and TNF-alpha play an important role in inflammatory reactions, we suggest that the defective production of IFN-gamma may be responsible for hyperproduction of IgE and the combined defect of IFN-gamma and TNF-alpha may contribute to the undue susceptibility to infections seen in patients with hyper-IgE syndrome.

T cells and cytokines in Crohn's disease.

Recent findings indicate that activated T lymphocytes, showing restricted T-cell receptor repertoire and a Th1-like profile of cytokine production, are responsible for macrophage activation and release of inflammatory cytokines, toxic oxygen metabolites and nitric oxide, which initiate and maintain the transmural intestinal inflammation in Crohn's disease. A critical event in the promotion of Th1-type response at gut level may involve up-regulation of IL-12 production and the breakdown of tolerance against the intestinal flora.

High intracytoplasmatic levels of Il-4 and Il-5 in a patient with Gleichs syndrome: case report.

Gleichs syndrome is characterized by recurrent localized angioedema, hypereosinophilia, elevated levels of IgM, rapid weight gain, itchy urticaria and fever. Little is known about the pathogenesis of this disease. Increased serum levels for IL5, IL6 and C5a have been reported before and during clinical exacerbations. In order to better understand the role of the T cells in Gleichs syndrome we analyzed the intracellular cytokine expression in CD3+ cells of a patient affected by the disease. As hypereosinophilia was documented, we asked whether IL-4 and IL-5 levels were increased, and the intracytoplasmatic expression of these Th2-cytokines was determined. The percentage of T lymphocytes (CD3-gated cells) of both CD8- and CD8+ phenotype expressing different cytokines showed an unusually high percentage of Th2-related cytokine (IL-4, IL-5 and IL-13) expressing T lymphocytes. The two new variants (myeloproliferative and lymphoproliferative) seem to account for hypereosinophilia in patients with hypereosinophilic syndrome (HES). In the lymphroliferative variant, the presence of a clonal CD3-CD4+ Th2 like lymphocyte secreting IL-4 and IL-5 in peripheral blood, may explain the hypereosinophilia and the hyper-IgE. In our study we show that the patient had a lymphoproliferative variant and her T cell had a Th2 type phenotype. Moreover, we suggest that Th2 lymphocytes may play a role in the pathogenesis of Gleichs syndrome. Further studies are needed to evaluate the possibility that a polyclonal aspecific activation of Th2 type cells can lead to hypereosinophilia, IgE production and the other manifestations typical of Gleichs syndrome.

In vivo CD30 expression in human diseases with predominant activation of Th2-like T cells.

CD30 is a member of the tumor necrosis factor (TNF) receptor family, originally described as a marker for Hodgkin and Reed-Sternberg cells in Hodgkin's disease, which has been found to be preferentially expressed by T cells producing Th2-type cytokines. The presence of CD30 expression was assessed by both immunohistochemistry and reverse transcriptase-polymerase chain reaction in the target organs of patients with Th1- or Th2-dominated disorders. CD30 expression was found in neither the gut of patients with Crohn's disease nor in the gastric antrum of Helicobacter pylori-infected patients, where there was high interferon-gamma (IFN-gamma) expression. In contrast, high CD30 expression in the apparent absence of IFN-gamma expression was observed in the skin of patients with systemic sclerosis or chronic graft versus host disease (GVHD), which can be considered Th2-dominated disorders. Moreover, high levels of soluble CD30 were found in the serum of both systemic sclerosis and GVHD patients but not in the serum of patients suffering from multiple sclerosis, a Th1-dominated disorder. Thus, CD30 expression appears to be preferentially associated with Th2-type responses not only in vitro but also in vivo.

T cell clones specific for Bet v I, the major birch pollen allergen, crossreact with the major allergens of hazel, Cor a I, and alder, Aln g I.

Tree pollens are responsible for type I allergies during the flowering season in spring. Pollens from birch, hazel and alder constitute the most important allergen sources in this respect in the northern hemisphere. Human IgE antibodies, specific for the major allergens of these pollens, are known to crossreact, and in general every tree pollen allergic patient is sensitized to these three pollen allergens. In this study we investigated eight T-helper cell clones (CD3+, CD4+, TCR alpha/beta) with specificity for Bet v I, the major birch pollen allergen, as proved by reactivity with purified natural as well as with recombinant allergen. The T cell clones were used to investigate common T cell epitopes of the Bet v I molecule with Cor a I, the major allergen of hazel pollen and Aln g I, the major allergen of alder pollen. All eight T cell clones reacted with all three proteins with different intensity. Moreover, three T cell clones, which were known to react with immunodominant T cell epitopes on the Bet v I molecule, were tested for reactivity with dodecapeptides synthesized according to the corresponding homologous regions of the Cor a I and Aln g I sequence. All the peptides induced strong T cell proliferation, indicating the existence of multiple cross-reacting epitopes. These findings will have an impact on the production of vaccines for immunotherapy of tree pollen allergies.

Cytolytic T lymphocytes with natural killer activity in thyroid infiltrate of patients with Hashimoto's thyroiditis: analysis at clonal level.

T Lymphocytes from thyroid infiltrates and peripheral blood (PB) of 3 patients with Hashimoto's thyroiditis (HT) were cloned using a microculture system previously shown to allow the clonal expansion of virtually all PB T lymphocytes from normal individuals. The phenotypic and functional features of a total number of 153 clones from thyroid infiltrates and 206 clones from PB were examined and compared with those of 272 clones derived from normal PB and spleens. The majority of clones derived from thyroid infiltrates of patients with HT had the cytotoxic/suppressor (T8+) phenotype, whereas the majority of clones from PB expressed the helper/inducer (T4+) phenotype. In addition, a consistent proportion (25%) of clones derived from PB of one patient had a phenotype (T3+T4-T8-) that was only occasionally found on clones obtained from PB or spleens of normal subjects. Most clones derived from both PB and thyroid infiltrates of the patients with HT had cytolytic activity, assessed by a lectin-dependent cytolytic assay against the murine P815 tumor cell line. The high frequency of cytotoxic T cells in thyroid infiltrates was related to the increased proportion of T8+ cells, whereas enhanced percentages of cytotoxic cell precursors with T4+ and T3+T4-T8- phenotypes primarily accounted for the high frequency of cytolytic T cells in the PB of the same patients. Many cytolytic T cell clones derived from thyroid infiltrates also had natural killer activity against human K562 and MOLT-4 target cells. These data provide the first functional analysis of T lymphocytes infiltrating the thyroid gland in patients with HT and suggest that the high proportions of cytolytic T cell precursors found in both thyroid infiltrates and PB of these patients may be of importance in determining the tissue damage in thyroid autoimmune disease.

CD4 + T Cells from Lymph Nodes Involved by Hodgkin's Disease Showing Response in Autologous Mixed Lymphocyte Reaction, are Polyclonal.

Thirteen CD4 + T cell clones (TCCs) showing autologous mixed lymphocyte reaction (AMLR) and 12 CD4 + AMLR-negative TCCs derived from involved lymph nodes (LN) of 4 untreated patients with newly-diagnosed Hodgkin's disease (HD) were analyzed for some functional activities and for T cell receptor (TCR) gamma and beta gene rearrangement The majority of the AMLR-positive-, but only two AMLR-negative TCCs showed cytolytic potential when assayed by a lectin-dependent assay. In addition, the proportion of clones able to produce interleukin 2 (IL-2) was higher among AMLR-positive- than AMLR-negative TCCs and the amount of IL-2 synthesized by AMLR-positive TCCs was significantly greater than that of AMLR-negative TCCs. In contrast, no difference in the profile of interleukin 4 (IL-4) and interferon-gamma (IFN-γ) production between AMLR-positive- and AMLR-negative TCCs was detected When AMLR-positive TCCs were analysed for their TCR beta and gamma gene rearrangements, a highly heterogeneous pattern was found. More importantly, TCCs derived from the same donor and displaying the same kind of TCR beta and gamma gene rearrangement showed different patterns of rearrangements, suggesting that CD4 + cells from LN involved by HD, displaying such an unusual functional profile, are polyclonal.

Thyroiditis as a model of organ specific autoimmune disease.

In the last few years a great deal of information on the etiopathogenetic aspects of organ-specific autoimmune diseases has been obtained from the extensive study of both animal models of experimental or spontaneous thyroiditis and of human thyroid autoimmune diseases. It has been clearly shown that genetic factors play a fundamental etiologic role. They are responsible for the dysregulation of the immune system and for the target organ susceptibility which favor the onset of the disease. Environmental factors are presumed to act as initiating or precipitating events, leading genetically predisposed individuals to thyroid autoimmunity. A number of immune mechanisms able to trigger autoimmune responses, such as antigenic cross-reactions and the aberrant expression of HLA class II molecules, have been suggested, but the definition of why and how they become operative requires further investigation. Data obtained from experimental models and from human thyroid diseases clearly indicate that the ongoing expansion of autoreactive T cells with specificity for thyroid autoantigens represents the main immunological event responsible for induction and maintenance of thyroid damage. Such autoreactive T cells can induce tissue lesions through activation of different effector systems and secretion of different combinations of lymphokines. In overt thyroid autoimmune diseases autoantibodies directed against functional molecules or cellular receptors can also be involved in the pathogenesis of tissue lesions. However, the pathogenesis of inflammatory destructive lesions of the thyroid is more complex and not yet fully elucidated. It is worthy of note that a large proportion of T cells present in inflammatory human thyroid infiltrates are apparently not directed against the thyroid autoantigens recognized so far.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of interleukins in induction and regulation of human IgE.

The studies on human IgE synthesis here summarized provide further insight into the cellular and molecular mechanisms involved in IgE regulation, as well as in the alterations responsible for IgE disregulation in some pathological conditions. They have clearly demonstrated that IL-4 is the essential factor for the induction of human IgE synthesis, since no substantial IgE production in vitro could be obtained in the absence of this lymphokine. Another T cell-derived lymphokine, IFN gamma, negatively regulates the IgE synthesis induced by IL-4. These two lymphokines can be produced by different T helper cells, as shown in mice, but they can also be the product of the same T cell clones. In such a case, the possibility that a given clone provides helper function for IgE seems to be dependent on the balance between the amounts of the two lymphokines produced. The IgE helper activity of rIL-4 appeared to be dependent on the presence in culture of appropriate concentrations of T lymphocytes, suggesting that T-B cell contact or other interleukins, such as IL-2 and IL-6, are needed in IL-4-dependent IgE synthesis. Finally, alterations of one or more of these regulatory mechanisms may play a crucial role in the pathogenesis of diseases characterized by a hyperproduction of IgE.

Diminished production of interleukin 2 and gamma-interferon by cloned "T" cells from patients with the acquired immunodeficiency syndrome (AIDS).

A total of 76 T-cell clones established from peripheral blood (PB) of 2 patients with the acquired immune deficiency syndrome (AIDS) and of 141 T-cell clones established from PB of 3 normal donors were compared for their ability to produce interleukin 2 (IL-2) and gamma-interferon (gamma-IFN). Twenty-seven clones from AIDS patients and 85 clones from controls expressed the CD4 phenotype, whereas 49 clones from AIDS patients and 56 clones from controls expressed the CD8 phenotype. There were no significant differences in the proportions of IL-2-producing CD4 T-cell clones established from PB of patients with AIDS and controls, but the mean concentration of IL-2 produced by CD4 clones from AIDS patients was significantly lower than that produced by CD4 clones from controls. Both the proportion of gamma-IFN-producing CD4 clones and the mean concentration of gamma-IFN produced by CD4 clones were significantly lower in AIDS patients than in controls. In contrast, there were no differences between AIDS patients and normal individuals in the proportion of IL-2- or gamma-IFN-producing CD8 clones, or in the mean concentration of IL-2 and gamma-IFN produced by CD8 clones. These data suggest that the reduced ability of PB T-cells from patients with AIDS to produce IL-2 and gamma-IFN is not simply due to altered proportions or numbers of T-cell subpopulations, but also reflects intrinsic abnormalities of individual CD4 T lymphocytes.