Clinical Manifestations Of Autoimmunity Research Articles

The Prevalence of Associated Autoimmune Diseases Among Adults With Type 1 Diabetes Mellitus: A Cross-Sectional Study

BackgroundThe relationship between type 1 diabetes mellitus (T1DM) and other autoimmune diseases has been known; however, the actual prevalence in the adult population nor clinical symptoms has not been determined locally.ObjectivesWe aim to determine the prevalence of associated autoimmune diseases (Hashimoto’s thyroiditis, celiac disease (CD), and adrenal insufficiency (AI)) and evaluate the most reporting symptoms and glycemic control assessment, as well as microvascular complications and hypoglycemia episodes.MethodsA cross-sectional study of 251 patients with T1DM at the diabetic clinic of King Abdulaziz Medical City in Riyadh (KAMC-RD), Saudi Arabia, was conducted. Autoimmune serologies including thyroid peroxidase (TPO) antibody and tissue transglutaminase IgA (tTG-IgA) antibody were checked with hormonal studies such as thyroid-stimulating hormone (TSH), morning serum cortisol, and short Synacthen test (SST) with duodenal biopsy results all were reviewed if present. Patients were directly interviewed to evaluate for the most common symptoms (including hypoglycemia episodes) for the preceding two weeks. Glycemic control was assessed by measuring glycated hemoglobin (HbA1c). Microvascular complications (i.e., nephropathy and retinopathy) were estimated by looking at the urine albumin/creatinine ratio (ACR) besides the ophthalmology’s visit notes.ResultsThe mean age was 26.3 ± 7.7 years, and the mean duration of diabetes at the time of data collection was 12.2 ± 7.6 years, whereas the mean HbA1c was 8.9% ± 1.8%. The prevalence of hypothyroidism was 16.3%, and TPO positivity was discovered in 58.6% of the tested patients (n = 70) with equal prevalence among both genders (p = 0.685). tTG-IgA were noticed among 16.4% of the patients (n = 164) without significant difference among gender. Serum cortisol test was performed among 128 patients; 28.1% had suboptimal levels, and 5.5% were deficient. Only four patients (n = 15) had suboptimal responses after SST. Nervousness and anxiety (p < 0.001), fatigue with weakness (p = 0.018), weight gain (p = 0.017), and cold intolerance (p = 0.005) were noted, which were statistically significantly higher among females. Weight gain was statistically significantly higher among the age group of >30 years (p = 0.036). For microvascular complication screening, ACR was collected in 199 (79.2%) participants, with a mean of 27.7 ± 155.9 mg/mmol. Only 10 (5%) patients had microalbuminuria, and 16 (8%) had macroalbuminuria; it was correlated significantly with diabetes duration (p = 0.045). A total of 132 (52.8%) patients were seen by ophthalmology, 28 (21.4%) had nonproliferative diabetic retinopathy (NPDR), and 10 (7.6%) has proliferative diabetic retinopathy (PDR) that significantly correlated with the duration of diabetes (p = 0.027). During patient interviews, 187 (74.5%) reported symptomatic hypoglycemia events that correlated significantly with glycemic control (p = 0.029).ConclusionAutoimmunity in Saudi adults with type 1 diabetes mellitus was significant with equal prevalence among both genders and age groups with no or slight difference. Clinical manifestations of autoimmunity were higher in women. Diabetes chronicity and poor glycemic control were the major complications; therefore, early glycemic control is advocated. Regular screening for autoimmunity and its complications is recommended for type 1 diabetic patients. Autoimmunity was found almost similar to previous literature.

Interpreting Rheumatology Laboratory Tests

Interpreting Rheumatology Laboratory Tests

Jakinibs for the Treatment of Immune Dysregulation in Patients With Gain–of–Function Signal Transducer and Activator of Transcription 1 (STAT1) or STAT3 Mutations

To investigate the efficacy of jakinib therapy in patients with gain-of-function (GOF) signal transducer and activator of transcription 1 (STAT1) or signal transducer and activator of transcription 3 (STAT3) mutations.The study included 17 total patients with either a STAT1 GOF (n = 11) or STAT3 GOF (n = 6) mutation who were treated with jakinibs (ruxolitinib or tofacitinib). Patients came from 11 international centers.This was a retrospective study to describe disease-related clinical manifestations and determine indication for treatment, dosage, length of treatment, treatment response, and treatment-associated complications. All subjects underwent thorough pre- and posttreatment clinical and laboratory evaluations and follow-up (follow-up period: 1–34 months).Fourteen patients (82%) responded favorably with clinical improvement to jakinib treatment. Observed clinical improvements included resolution of enteropathy leading to total parenteral nutrition independence, better lung function, improved autoimmune cytopenias, decreased arthritis symptoms, and remission of hemophagocytic lymphohistiocytosis. All patients with STAT1 GOF had resolved chronic mucocutaneous candidiasis with treatment. Most patients tolerated the jakinibs well with minimal or transient adverse effects. An increase in herpes zoster infections (none systemic and all cleared with antiviral agents) was observed in some patients. Four patients died despite treatment with a jakinib. The majority of these patients were critically ill with severe invasive infection or progressive lung disease. One patient died due to posttransplant complications.Jakinibs are both safe and effective in the treatment of patients with STAT1 or STAT3 GOF mutations with clinical manifestations of autoimmunity and/or immune dysregulation.Patients with STAT1 and STAT3 GOF mutations often present in early childhood with severe and/or refractory infections, lymphoproliferation, autoinflammation, and autoimmunity. Jakinibs allow for a targeted therapeutic approach to block the cytokine-induced JAK activation in STAT1 and STAT3 GOF diseases. This is the first study to evaluate the use and clinical impact of jakinibs in STAT1 and STAT3 GOF. The results are overwhelmingly encouraging, with the majority of patients having clinical improvement and reduction or resolution of autoimmune manifestations after treatment with a jakinib. Use of jakinibs late in disease progression or when critically ill was associated with mortality, suggesting early initiation may improve efficacy. This study has significant clinical impact in the treatment of STAT1 and STAT3 GOF and reinforces the notion that early genetic diagnosis of primary immunodeficiency diseases may lead to targeted therapeutic options and improved clinical outcomes.

The Epidemiology and Clinical Manifestations of Autoimmunity in Selective IgA Deficiency.

Selective immunoglobulin A deficiency (SIgAD) is the most common primary immunodeficiency, defined as an isolated deficiency of IgA (less than 0.07g/L). Although the majority of people born with IgA deficiency lead normal lives without significant pathology, there is nonetheless a significant association of IgA deficiency with mucosal infection, increased risks of atopic disease, and a higher prevalence of autoimmune disease. To explain these phenomena, we have performed an extensive literature review to define the geoepidemiology of IgA deficiency and particularly the relative risks for developing systemic lupus erythematosus, hyperthyroidism, hypothyroidism, type 1 diabetes mellitus, Crohn's disease, ulcerative colitis, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, and vitiligo; these diseases have strong data to support an association. We also note weaker associations with scleroderma, celiac disease, autoimmune hepatitis, immune thrombocytopenic purpura, and autoimmune hemolytic anemia. Minimal if any associations are noted with myasthenia gravis, lichen planus, and multiple sclerosis. Finally, more recent data provide clues on the possible immunologic mechanisms that lead to the association of IgA deficiency and autoimmunity; these lessons are important for understanding the etiology of autoimmune disease.

Safety and Clinical Benefit of Lentiviral Hematopoietic Stem Cell Gene Therapy for Wiskott-Aldrich Syndrome

Wiskott-Aldrich Syndrome (WAS) is an X-linked primary immunodeficiency characterized by thrombocytopenia, recurrent infections, eczema, autoimmunity and increased susceptibility to malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) is a recognized curative treatment for WAS, but is still associated with transplant-related complications and long-term morbidity, particularly in the absence of fully matched donors. In April 2010, we initiated a phase I/II clinical trial with hematopoietic stem cell (HSC) gene therapy (GT) for WAS. The investigational medicinal product (IMP) consists of autologous CD34+ HSC engineered with a lentiviral vector (LV) driving the expression of WAS cDNA from an endogenous 1.6 kb human WAS promoter (LV-WAS), infused after a reduced intensity conditioning (RIC) based on anti-CD20 mAb, targeted busulfan and fludarabine. We previously reported early follow up (FU) results from the first 3 patients (Aiuti et al., Science 2013). Seven patients (Zhu score ≥3) have now been treated at a median age of 1.9 years (1.1 - 11.1). As of May 2015, all patients are alive with a median FU of 3.2 years (0.7 - 5.0). CD34+ cell source was bone marrow (BM) (n=5), mobilized peripheral blood (MPB) (n=1) or both (n=1). IMP dose ranged between 7.0 and 14.1 x106 CD34+/kg, containing on average 94.4 ± 3.5% transduced clonogenic progenitors and a mean vector copy number (VCN)/genome in bulk CD34+ cells of 2.7 ± 0.8. No adverse reactions were observed after IMP infusion and RIC was well tolerated. Median duration of severe neutropenia was 19 days; granulocyte-colony stimulating factor was administered to 1 patient.In the first 6 treated patients with FU >2 years, we observed robust and persistent engraftment of gene corrected cells. At the most recent FU, transduced BM progenitors ranged between 20.7 and 59.7%, and LV-transduced cells were detected in multiple lineages, including PB granulocytes (VCN 0.34 - 0.93) and lymphocytes (VCN 1.18 - 2.73). WAS protein expression, measured by flow-cytometry, was detected in the majority of PB platelets [mean ± standard deviation (SD), 71.4 ± 14.0%], monocytes (63.3 ± 18.5%) and lymphocytes (78.9 ± 14.9%). Lymphocyte subset counts were normal in most patients and proliferative response to anti-CD3 mAb was in the normal range in all 6 patients.After immune reconstitution, a marked reduction in the annualized estimated rate of severe infections was observed, as compared with baseline (figure 1A). The first 6 treated patients discontinued anti-infective prophylaxis and no longer require a protected environment. Four patients stopped immunoglobulin supplementation and 2 of them developed specific antibodies after vaccination. Eczema resolved in 4 patients and remains mild in 2. No clinical manifestations of autoimmunity were observed ≥1 year after GT in accordance with improved B-cell development and decreased autoantibody production. All patients became platelet transfusion independent at a median of 4 months after GT (range: 1.0 - 8.7). Mean platelet counts progressively increased after treatment (mean ± SD: before GT, 13.4 ± 7.8 x109/l; 24-30 month FU, 45.8 ± 22.0 x109/l; 36-42 month FU, 57.0 ± 18.7 x109/l).The frequency and the severity of bleeding events decreased after the 1st year of FU. No severe bleedings were recorded after treatment (figure 1B).Quality of life improved in all patients after GT. From the 2nd year of FU, the number of hospitalizations for infections decreased and no hospitalizations due to bleeding were observed after treatment.The seventh patient treated, who received MPB derived CD34+ cells only, showed the fastest platelet recovery with the highest level of transduced myeloid cell engraftment, and is clinically well.No Serious Adverse Events (SAE) related to the IMP were observed. The most frequent SAE were related to infections (85%), occuring mainly during the 1st year of FU.Importantly, no evidence of abnormal clonal proliferations emerged after GT and the LV integration profile show a polyclonal pattern, with no skewing for proto-oncogenes.In conclusion, this updated report in 7 WAS patients show that GT is well tolerated and leads to a sustained clinical benefit. The high level of gene transfer obtained with LV-WAS results in robust engraftment of transduced HSC, even when combined with RIC. Prolonged FU will provide additional information on the long-term safety and clinical efficacy of this treatment. [Display omitted] DisclosuresVilla:Fondazione Telethon: Research Funding. Dott:GlaxoSmithKline: Consultancy. van Rossem:GlaxoSmithKline: Employment. Naldini:Salk Institute: Patents & Royalties: Lentiviral vectors; San Raffaele Telethon Institute: Patents & Royalties: Lentiviral vector technology; GlaxoSmithKline: Other: GSK licensed gene therapies developed at my Institute and the Institute receives milestone payments; Sangamo Biosciences: Research Funding; Biogen: Research Funding; Genenta Sciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Aiuti:GlaxoSmithKline (GSK): Other: PI of clinical trial which is financially sponsored by GSK; Fondazione Telethon: Research Funding.

Large Granular Lymphocyte Infiltration in the Bone Marrow in Children and Young Adults May Suggest Primary Immune Deficiency

Large granular lymphocyte (LGL) leukemia is a group of rare lymphoproliferative disorders which involve inappropriate clonal expansion of either cytotoxic T-lymphocytes (CTLs) or natural killer cells (NK). The usual age at onset is between 40 to 60 years. We here describe four very young patients showing LGL infiltration in the bone marrow (BM) and all diagnosed with primary immune deficiency.Patient 1 is a 13-year old male who presented with gingivostomatitis, but no severe infections, autoimmune disease or allergies. He had persistent leukopenia (1.9x109/L), neutropenia (<0.05x109/L), thrombocytopenia (60-80x109/L) and mild anemia. The BM showed myeloid maturation arrest and infiltration of LGL cells with NK cell phenotype (CD3-, CD2+, CD16+, CD56-/+, CD57-, CD4-, CD8-) at 50% of the BM cellularity. In peripheral blood (PB) T, B and NK cell counts were normal. However, low levels of monocytes (0.09x109/L), normal levels of monocytoid (2.7x106/L) and low levels of plasmacytoid (0.1x106/L) dendritic cells (DC) were detected. While germline whole exome sequencing (WES) did not identify mutations likely to cause the disease, targeted sequencing of GATA2 mRNA showed uniallelic GATA2 expression, confirming haploinsufficiency.Patient 2 is a 15-year old female who has neonatal diabetes, autoimmune desquamative interstitial pulmonary disease, autoimmune enteropathy, exocrine pancreatic insufficiency and delayed growth. She developed transfusion-dependent, Coombs-negative anemia at age of 15. In the PB, 50% of the lymphocytes were LGLs. BM showed pure red cell aplasia plus LGL infiltration of TCRgd positive T cells (CD3+, CD2+, CD5+, CD8-/+, CD4-/+, CD57+) at 43% of BM cellularity. Clonal TCRg rearrangement was detected. Hypogammaglobulinemia presented at age of 7. T, B and NK cell counts were low normal, but DCs were non-existent. WES and functional studies revealed a germline gain-of-function mutation of STAT3 gene.Patient 3 is 42-year old female who has had severe infections (bacterial, viral and protozoan) starting at the age of 4 months. From age of 9, autoimmune manifestations occurred with immune thrombocytopenia, neutropenia and anemia, and intensively positive rheumatoid factor. Since age of 17, CD8+ LGLs were detected in PB reaching level of 50% of lymphocytes. In the BM, CD3+CD5-CD56- T -lymphocyte infiltration with clonal TCRd rearrangement was detected. In her 30ies she developed pulmonal arterial hypertension and hypogammaglobulinemia (0.8 g/L). She has low counts of B cells (0.02x109/L), and monocytoid (1.9x106/L) and plasmacytoid (0) DCs. WES identified a homozygous germline missense mutation in CECR1 gene, leading to total loss-of-function of the encoded adenosine deaminase 2 (ADA2) protein.Patient 4 presented with waxing and waning skin nodules from age of 10 years, but no severe infections or allergies. At age of 26, she was diagnosed with hemolytic anemia with spherocytosis, splenomegaly and cholelithiasis. Five years later remarkable hepatomegaly, and clinical autoimmune manifestations with SLE-type skin lesions, autoimmune hemolytic anemia and iritis were observed. Complement C3 (0.17 g/l) and C4 (<0.02 g/L) and NK cell (0.081) levels were low, but CD3, CD8 and CD4 counts and IgM and IgG levels were increased. T-cell infiltration was shown in the skin nodules and liver. BM showed mildly decreased myelo- and erythropoiesis and T cell infiltration (CD3+, CD8+, CD7+, CD45RO+, BCL2+, CD56-) up to 70% of the BM cellularity consistent with LGL infiltration. WES identified the same germline missense mutation in CECR1 gene as seen in patient 3, and a functional analysis showed no ADA2 activity.We conclude that LGL lymphoproliferation in young patients is often a sign of underlying primary immunodeficiency, highlighting the need for detailed genetic studies in these cases.Table 1PatientAge at LGLLGL in PB(109/L)LGL immune-phenotypeClonalityBM LGL infiltrationClinicalPID1130.38NKNA40%N,THepatomegalyGATA2 deficiency2151.79CTLTCRg43%AutoimmunityAHepatosplenomegalySTAT3 hyperactivation3171,49CTLTCRdNAN,T, AAutoimmunityPulmonary arterial hypertensionADA2 deficiency431NACTLTCRg weak40%AutoimmunityHepatosplenomegalyHepatopulmonal syndromeADA2 deficiencyA, anemia; N, neutropenia, CTL, cytotoxic T cell; LGL, large granular lymphocyte; NK, natural killer cell; PID, primary immune deficiency; TCR, T cell receptor; T, thrombocytopenia DisclosuresMustjoki:Signe and Ane Gyllenberg Foundation: Research Funding; Finnish Cancer Institute: Research Funding; Sigrid Juselius Foundation: Research Funding; Academy of Finland: Research Funding; the Finnish Cancer Societies: Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Siitonen:Pzizer: Other: charges of EAHAD congress 2015; Novartis: Other: charges of EHA congress 2015. Saarela:Roche: Honoraria.

Expanding the spectrum of recombination-activating gene 1 deficiency: A family with early-onset autoimmunity

Expanding the spectrum of recombination-activating gene 1 deficiency: A family with early-onset autoimmunity

Heat-Shock Proteins in Autoimmunity

Heat-Shock Proteins in Autoimmunity

Autoimmune Antibodies and Recurrence-Free Interval in Melanoma Patients Treated With Adjuvant Interferon

Appearance of autoantibodies and clinical manifestations of autoimmunity in melanoma patients treated with adjuvant interferon (IFN)-alpha2b was reported to be associated with improved prognosis. We assessed the association of the appearance of autoantibodies after initiation of treatment with recurrence-free interval in two randomized trials that compared intermediate doses of IFN with observation for the treatment of melanoma patients. Serum levels of anticardiolipin, antithyroglobulin, and antinuclear antibodies were determined using enzyme-linked immunosorbent assays in 187 and 356 patients in the European Organization for Research and Treatment of Cancer (EORTC) 18952 and Nordic IFN trials, respectively, immediately before and up to 3 years after random assignment. The association of the presence of at least one of the three autoantibodies with risk of recurrence was assessed by three Cox models in patients negative for all three autoantibodies at baseline (125 from the EORTC 18952 trial and 230 from the Nordic IFN trial): 1) a model that considered appearance of autoantibodies as a time-independent variable, 2) one that considered a patient autoantibody positive once a positive test for an autoantibody was obtained, and 3) a model in which the status of the patient was defined by the most recent autoantibody test. All statistical tests were two-sided. When treated as a time-independent variable (model 1), appearance of autoantibodies was associated with improved relapse-free interval in both trials (EORTC 18952, hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.25 to 0.68, P < .001; and Nordic IFN, HR = 0.51, 95% CI = 0.34 to 0.76, P < .001). However, on correction for guarantee-time bias, the association was weaker and not statistically significant (model 2: EORTC 18952, HR = 0.81, 95% CI = 0.46 to 1.40, P = .44; and Nordic IFN, HR = 0.85, 95% CI = 0.55 to 1.30, P = .45; model 3: EORTC 18952, HR = 1.05, 95% CI = 0.59 to 1.87, P = .88; and Nordic IFN, HR = 0.78, 95% CI = 0.49 to 1.24, P = .30). In two randomized trials of IFN for the treatment of melanoma patients, appearance of autoantibodies was not strongly associated with improved relapse-free interval when correction was made for guarantee-time bias.

Autoimmunity as a prognostic factor in melanoma patients treated with adjuvant low‐dose interferon alpha

Interferon alpha is used for the adjuvant treatment of malignant melanoma at different dosages (high-, intermediate-, low-dose therapy). Only a minority of patients might benefit from this therapy, and markers to identify such patients are missing. A recent study suggested that melanoma patients developing autoantibodies or clinical manifestations of autoimmunity during adjuvant high-dose interferon alpha treatment had a significant survival benefit. We retrospectively reviewed 134 melanoma patients from our institution treated with adjuvant low-dose interferon alpha therapy and correlated the development of autoimmune diseases with prognosis. Interferon (IFN) therapy was routinely monitored by history, physical examination and laboratory tests before, after the first month and then after every 3 months of therapy. During a median follow up of 46.0 months (8.5-79.0 months) 28 patients (20.9%) suffered from recurrences and melanoma related deaths occurred in 16 patients (11.9%). In 20 patients (14.9%) autoimmune thyroiditis (AIT) was diagnosed during IFN therapy, one of these 20 patients developed rheumatoid arthritis later while continuing IFN therapy. Other autoimmune diseases were not observed. In 2 patients (one with AIT and one with arthritis) the autoimmune disease led to discontinuation of IFN therapy, in the other patients AIT remained subclinical or responded well to treatment while IFN therapy was continued. Kaplan-Meier analyses revealed a significant better recurrence free survival and a trend for a better overall survival for patients with AIT. Thus, autoimmunity triggered by low-dose IFN therapy appears to indicate an improved prognosis and should encourage continuation of IFN therapy.

Controversies on autoimmunity and prognosis in cancer

Sir, The presence of CD4+CD25+ regulatory T cells (Treg) in cancer patients might be, in part, responsible for downregulation of antitumour immune responses. Schaefer et al (2005) have shown the importance of Treg in defining the immune profile of cancer patients, illustrating the role of these cells in downregulating functions of other T-cell subsets. Their hypothesis was that lymphocyte homeostasis disrupted by the presence of tumour fails to normalise following successful therapy. Wei et al (2005) recently assessed the possible synergy of immune reactivity to defined tumour- and self-antigens following reduction of CD4+CD25+ Treg. In a Treg-deprived environment, tumour cells primed the immune system, with consequent tumour regression. Treg-depletion enhanced autoimmunity to mouse thyroglobulin (mTg) in resistant BALB/c mice. Concurrent tumour regression and mTg immunisation resulted in further elevation of both antitumour and anti-mTg immunity. There are various inhibitory mechanisms in T cells to prevent pathological autoimmunity. Blocking CTLA4 on T cells or depleting CD25+ Treg is sufficient to break self tolerance, causing nonspecific autoimmune pathologies (Phan et al, 2003). On the other hand, an association between autoimmunity and a favourable antitumour effect has been reported. Anti-CTLA-4 Ab given to patients with metastatic melanoma induces durable objective clinical responses associated with the induction of autoimmune side effects. The autoimmune and antitumour effects seen after CTLA-4 blockade appear to act through direct activation of CD4+ and CD8+ effector cells. In addition, inhibition of a signaling inhibitor in antigen-loaded dendritic cells (DCs) can induce a tumour-associated antigen-specific pathological autoimmune response against tumour. SOCS1-silenced DCs effectively break tolerance at the host level and cause self antigen-specific autoimmune pathologies against normal tissues but also against tumours (Evel-Kabler et al, 2006). As interferon alfa-2b has the ability to induce an immune response against autoantigens with serologic and clinical manifestations of autoimmunity, it is possible that it also induces an immune response against tumours. The appearance of autoantibodies or clinical manifestations of autoimmunity during treatment with high-dose adjuvant interferon alfa-2b was associated with statistically significant improvements in relapse-free survival and overall survival (Gogas et al, 2006). By contrast, the early presence of autoantibodies in the serum has been described to correlate with an unfavourable prognosis (de Visser et al, 2006). The occurrence of autoantibodies in the serum of cancer patients, and interstitial antibody deposition in human tumours have been widely reported. As CD4+ and CD8+ T-lymphocytes are important modulators of tissue-damaging B-lymphocyte responses, considered that Ig deposition occurs in human premalignant and malignant tissues, imbalanced adaptive-immune-cell interactions could represent underlying mechanisms that regulate the onset of chronic inflammation associated with cancer development (de Visser et al, 2006). While it could be possible to use autoimmune responses as surrogate markers to evaluate new treatments (Gogas et al, 2006), it might be highlighted that individuals with progressive tumours could produce a higher antigen load, therefore triggering greater antibody deposition (de Visser et al, 2006).

Reply: Controversies on autoimmunity and prognosis in cancer

Sir, In their letter, Dr Ferretti and co-worker refer to the perception that autoimmunity and cancer are related and may represent ‘two sides of the same coin'. While this concept is not new to immunologists, it has surfaced in recent years largely due to accumulating evidence that more effective immunotherapy of cancer is associated with autoimmune sequelae, which may cause substantial pathology (Attia et al, 2005; Korman et al, 2005). These recent observations coming from animal experiments and human clinical trials once again bring to our attention the crucial role of immune regulation in disease development and progression. While autoimmunity has always been linked to immune dysregulation, cancer development is viewed as progressive accumulation of genetic abnormalities in malignant cells, with the immune system allowing or even promoting its progression (Balkwill et al, 2005; de Visser et al, 2006). Further, the tumours, like viruses, have evolved numerous ways of escape from immune surveillance, as recently reviewed, so that the host immune system is either disarmed or unable to recognise the tumour (Whiteside, 2006). As Dr Ferretti and co-worker point out, regulatory T cells (Treg) represent only one mechanism of tumour escape, but one that is clearly relevant to both autoimmunity and cancer. Treg have been shown to regulate autoimmunity (Paust and Cantor, 2005; Sakaguchi, 2005). More recently, Treg accumulating at tumour sites and in the circulation of patients with cancer (Curiel et al, 2004; Schaefer et al, 2005) are considered to be responsible for dampening antitumour immune defences in an antigen-specific manner (Zhou et al, 2006). The cellular and molecular mechanisms responsible for this downregulation of antitumour immunity by Treg are under intense scrutiny today, but an emerging concept appears to be that the self-nature of tumour-associated antigens may be the trigger. Self-epitopes overexpressed by tumours could provide signals for Treg expansion and their accumulation/activation at tumour sites. However, Treg are a heterogeneous population encompassing natural Treg as well as IL-10-induced and antigen-dependent Tr1 cells and perhaps other subsets (Levings and Roncarolo, 2005). It is yet to be determined which of these are responsible for abetting cancer escape vs downregulating autoimmunity. The discovery that Treg can be expanded many fold in the presence of rapamycin (1 nM) provides us with a potential therapeutic tool in ameliorating autoimmunity (Battaglia et al, 2005; Strauss et al, 2006). In human cancer, rapamycin-driven expansion of Treg provides the means of evaluating these cells at a scale not possible with ex vivo isolated Treg subsets of CD4+CD25+ T cells. These strategies are likely to clarify the functional attributes of Treg and their contributions to disease progression. The question of how Treg are regulated is also important, and the answer when available might reinforce the connection between cancer and autoimmunity as well as uncover further complexity of immune interactions. The role DC play in modulating T-cell activation is well known. It now appears that DC may also crosstalk with Treg (Chen, 2006). SOCS-1-silenced DC have been shown to effectively break tolerance to self and promote antitumour responses (Evel-Kabler et al, 2006). Thus, molecular signals that DC experience in the microenvironment determine their discourse with cognate T cells. The outcome of this discourse may well depend on the microenvironment, including tissue- and/or tumour-derived factors, especially cytokines and chemokines. The pleiotropic effects of these soluble mediators are known to include Treg and other types of immune cells (Zhang et al, 2005). The local tumour/tissue microenvironment with its autocrine and paracrine cytokine signalling networks is bound to orchestrate DC regulation as well as Treg activation and, therefore, is of critical importance for disease progression. In patients with melanoma, the appearance of autoantibodies or clinical manifestations of autoimmunity during therapy with interferon α-2B is associated with good prognosis and improved survival (Gogas et al, 2006). The mechanisms responsible for breaking tolerance to self and simultaneously upregulating antitumour immunity are presently unclear. A link(s) between cancer and autoimmunity may operate at the cellular level (ie, DC or Treg) and may involve cytokine networks or signalling pathways such as the NF-κB pathway known to regulate proinflammatory cytokine responses (Perkins, 2004). Nevertheless, the predictive value of autoimmune phenomena in the upregulation of antitumour immunity strongly suggests that some common immune mechanisms are involved. Dr Ferretti and co-worker are correct in reminding us that it will be necessary and challenging to identify these mechanisms in order to skilfully balance the therapeutic interface between cancer and autoimmunity.

Strategies for the Development of More Effective Adjuvant Therapy of Melanoma: Current and Future Explorations of Antibodies, Cytokines, Vaccines, and Combinations

Adjuvant trials have evaluated the influence of multiple agents on relapse and mortality for patients with intermediate-risk (stage IIA, American Joint Committee on Cancer staging manual, 6th ed.), high-risk (stage IIB-III), or very high-risk (stage IIIB-IV) operable melanoma. A 25% to 33% reduction of relative relapse risk with high-dose IFN-alpha2b therapy has been documented in stage groups overall, with survival prolongation in two of these trials. In contrast, no large cooperative group trial has ever shown a significant prolongation of survival for inoperable advanced stage IV melanoma. The basis for the failure of therapies in advanced disease may lie in differences in the immune function of patients with active metastatic stage IV disease. These observations argue for the exploration of promising new therapies in adjuvant settings. Past adjuvant studies have targeted stage IIB-III patients, focusing less on the more advanced but resectable stage IIIB and IV (M(1a-b)) disease groups. Current chemobiotherapy (S0008) and granulocyte-macrophage colony-stimulating factor plus peptide vaccination (E4697) trials have now evaluated the higher-risk disease groups where trials may soon be expected to yield results. Predictive markers that would allow us to focus treatment on those patients who are most likely to respond would accelerate our development of adjuvant therapy for melanoma. We have recently developed a neoadjuvant approach to high-dose IFN in which the molecular and immunologic effects of IFN have been correlated with clinical antitumor effects of this therapy. In addition, the Hellenic Oncology group has shown that the benefit of high-dose IFN is closely correlated with serologic and clinical manifestations of autoimmunity. These new insights will allow us to develop more efficient approaches to adjuvant therapy of melanoma, focusing on autoimmunity and antitumor immunity with new immunomodulators, such as anti-CTLA4 antibodies and vaccination.

Prognostic Significance of Autoimmunity during Treatment of Melanoma with Interferon

Immunotherapy for advanced melanoma induces serologic and clinical manifestations of autoimmunity. We assessed the prognostic significance of autoimmunity in patients with stage IIB, IIC, or III melanoma who were treated with high-dose adjuvant interferon alfa-2b. We enrolled 200 patients in a substudy of a larger, ongoing randomized trial. Blood was obtained before the initiation of intravenous interferon therapy, after 1 month of therapy, and at 3, 6, 9, and 12 months. Serum was tested for antithyroid, antinuclear, anti-DNA, and anticardiolipin autoantibodies, and patients were examined for vitiligo. The median duration of follow-up was 45.6 months. Relapse occurred in 115 patients, and 82 patients died. The median relapse-free survival was 28.0 months, and the median overall survival was 58.7 months. Autoantibodies and clinical manifestations of autoimmunity were detected in 52 patients (26 percent). The median relapse-free survival was 16.0 months among patients without autoimmunity (108 of 148 had a relapse) and was not reached among patients with autoimmunity (7 of 52 had a relapse). The median survival was 37.6 months among patients without autoimmunity (80 of 148 died) and was not reached among patients with autoimmunity (2 of 52 died). In univariate and multivariate regression analyses, autoimmunity was an independent prognostic marker for improved relapse-free survival and overall survival (P<0.001). The appearance of autoantibodies or clinical manifestations of autoimmunity during treatment with interferon alfa-2b is associated with statistically significant improvements in relapse-free survival and overall survival in patients with melanoma.

Spondyloenchondrodysplasia with spasticity, cerebral calcifications, and immune dysregulation: Clinical and radiographic delineation of a pleiotropic disorder

Enchondromas are a feature of several constitutional disorders of bone, and the classification of different nosologic entities is still provisional. Among these disorders, spondyloenchondrodysplasia (SPENCD), as outlined by Schorr et al. [1976], is defined by the presence of radiolucent spondylar and metaphyseal lesions that represent persistence of islands of chondroid tissue within bone. Careful review of radiographic findings is needed to distinguish SPENCD from the many other disorders combining enchondromas with spinal lesions. Even when strict criteria are applied, it appears that SPENCD is clinically heterogeneous, as some SPENCD patients are neurologically intact while others present with spasticity, mental retardation, and cerebral calcifications in different combinations, and it has been suggested that SPENCD should be divided in two types. We herein report ten individuals from six families with SPENCD and illustrate the radiographic changes. Seven individuals had CNS manifestations including spasticity, developmental delay, and late-onset cerebral calcifications. We also noted that six individuals had clinical manifestations of autoimmunity (auto-immune thrombocytopenic purpura, auto-immune hemolytic anemia, auto-immune thyroiditis, and SLE) and one had been diagnosed with immune deficiency. Neurological and autoimmune manifestations were seen in different combinations within one single family. These observations suggest that SPENCD may be a single entity defined by specific radiographic features, but with remarkably pleiotropic manifestations that include CNS disease (spasticity, mental retardation, and calcifications), as well as immune dysregulation ranging from autoimmunity to immunodeficiency. The notion of recessive inheritance hitherto assumed is challenged by the observation of two apparently dominant pedigrees.

Autoimmunity and Hypercoagulability in Anderson Fabry Patients from Argentina.

Autoimmunity secondary to chronic immunostimulation by glucocerebrosides has been reported in Gaucher disease, as well as in Anderson Fabry disease (AFD) by others and us.AIMS: To get further insight on this association, we looked for antinuclear and antiphospholipid-related autoantibodies in a series of AFD Argentine patients.METHODS/PATIENTS: 35 patients, 16 hemizygous and 19 heterozygous from 4 families, were studied for: 1) autoantibodies to extractable nuclear antigens (ENAs): (SSA/RO, SSB/La, Sm/RNP, and Jo-1); 2) anti-double stranded DNA (dsDNA), and 3) antiphospholipid antibodies: lupus anticoagulant (LA), anticardiolipin antibodies (ACA), and antiphosphatidylserine antibodies, (APA).RESULTS: At least one autoantibody was detected in 18 patients (51.4%). They were more frequent found in hemizygous (68.8%) than in heterozygous (42.1%). Elevated titers of ENAs were seen in 11.4% (n=4). Positive for LA were 34.3% (n=12) and for ACA 14.3% (n=5). Three patients shared two autoimmune markers. Anti dsDNA and APA were never present.CONCLUSIONS:There was an unexpected high incidence of autoimmune responses: one every two AFD patients showed at least one autoantibody;They were more frequent in hemizygous than in heterozygous cases.The pathologic implications of their presence is still not known, although it is probable that antiphospholipid antibodies contribute to hypercoagulability in AFD.Autoimmunity seems to play an important role in some pathogenic disturbances seen in other lysosomal storage diseases. So, humoral/clinical correlations should be followed closely to detect the eventual outcome of collagen diseases or other clinical manifestations of autoimmunity in AFD.

Aberrant T-Cell Antigen Receptor-Mediated Responses in Autoimmune Lymphoproliferative Syndrome

Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of defective lymphocyte apoptosis due to mutations of the Fas receptor and other molecules in the Fas signaling pathway. In addition to accumulation of CD4 − CD8 − double-negative (DN) T cells, many patients display a dysregulated cytokine pattern with dysfunctional T cells, suggesting Fas defects may impact pathways of T-cell activation/differentiation. Here, we report two novel mutations in the Fas receptor resulting in an ALPS phenotype. Utilizing flow cytometry, we found anti-CD3 activated CD4 + T cells from these patients were incapable of fully upregulating activation markers (CD25, CD69, and CD40L) or producing interferon-γ and IL-2. Additionally, DN T cells were unable to transduce proximal T-cell antigen receptor signals or produce cytokines. Furthermore, DN T cells overexpressed CD57 and phenotypically resembled end-stage effector cells. As DN T cells were essentially anergic, the clinical manifestations of autoimmunity are more likely to be a consequence of aberrant cytokine secretion within the CD4 + T-cell subpopulation.

Polychondrite chronique atrophiante et syndrome myélodysplasique. À propos de deux observations

Biological or clinical auto-immune manifestations have been frequently reported in myelodysplastic syndromes and could be the result of a polyclonal B lymphocytes activation. We report on 2 exceptional cases of the association of myelodysplastic syndrome and relapsing polychondritis.