Intravenous Immunoglobulins Promote an Expansion of Monocytic Myeloid-Derived Suppressor Cells (MDSC) in CVID Patients.

Common variable immunodeficiency disorders (CVID), the most common primary immune deficiency, includes heterogeneous syndromes characterized by hypogammaglobulinemia and impaired antibody responses. CVID patients frequently suffer from recurrent infections and inflammatory conditions. Currently, immunoglobulin replacement therapy (IgRT) is the first-line treatment to prevent infections and aminorate immune alterations in CVID patients. Intravenous Immunoglobulin (IVIg), a preparation of highly purified poly-specific IgG, is used for treatment of immunodeficiencies as well as for autoimmune and inflammatory disorders, as IVIg exerts immunoregulatory and anti-inflammatory actions on innate and adaptive immune cells. To determine the mechanism of action of IVIg in CVID in vivo, we determined the effect of IVIg infusion on the transcriptome of peripheral blood mononuclear cells from CVID patients, and found that peripheral blood monocytes are primary targets of IVIg in vivo, and that IVIg triggers the acquisition of an anti-inflammatory gene profile in human monocytes. Moreover, IVIg altered the relative proportions of peripheral blood monocyte subsets and enhanced the proportion of CD14+ cells with a transcriptional, phenotypic, and functional profile that resembles that of monocytic myeloid-derived suppressor cells (MDSC). Therefore, our results indicate that CD14 + MDSC-like cells might contribute to the immunoregulatory effects of IVIg in CVID and other inflammatory disorders.

Sublingual Bacterial Vaccination Reduces Recurrent Infections in Patients With Autoimmune Diseases Under Immunosuppressant Treatment.

Introduction: Conventional or biologic disease-modifying anti-rheumatic drugs (DMARDs) are the mainstay of treatment for systemic autoimmune disease (SAD). Infectious complications are a major concern in their use. Objective: To evaluate the clinical benefit of sublingual mucosal polybacterial vaccines (MV130 and MV140), used to prevent recurrent respiratory and urinary tract infections, in patients with SAD and secondary recurrent infections following conventional or biologic DMARDs. Methods: An observational study in SAD patients with recurrent respiratory tract infections (RRTI) and/or recurrent urinary tract infections (RUTI) was carried out. All patients underwent mucosal (sublingual) vaccination with MV130 for RRTI or with MV140 for RUTI daily for 3 months. Clinical evaluation was assessed during 12 months of follow-up after the first dose, i.e., 3 months under treatment and 9 months once discontinued, and compared with the previous year. Results: Forty-one out of 55 patients completed 1-year follow-up. All patients were on either conventional or biologic DMARDs. A significant decrease in the frequency of RUTI (p<0.001), lower respiratory tract infections (LRTI) (p=0.009) and upper respiratory tract infections (URTI) (p=0.006) at 12-mo with respect to the previous year was observed. Antibiotic prescriptions and unscheduled medical visits decreased significantly (p<0.020) in all groups. Hospitalization rate also declined in patients with RRTI (p=0.019). The clinical benefit demonstrated was concomitant to a significant increase in both anti-S. pneumoniae IgA and IgG antibodies following MV130 vaccination. Conclusions: Sublingual polybacterial vaccines prevent recurrent infections in patients with SAD under treatment with immunosuppressant therapies, supporting a broad non-specific anti-infectious effect in these patients.

Antiphospholipid Antibodies Overlapping in Isolated Neurological Syndrome and Multiple Sclerosis: Neurobiological Insights and Diagnostic Challenges.

Antiphospholipid syndrome (APS) is characterized by arterial and venous thrombosis, pregnancy morbidity and fetal loss caused by pathogenic autoantibodies directed against phospholipids (PL) and PL-cofactors. Isolated neurological APS may represent a significant diagnostic challenge, as epidemiological, clinical and neuroimaging features may overlap with those of multiple sclerosis (MS). In an open view, MS could be considered as an organ-specific anti-lipid (phospholipid and glycosphingolipid associated proteins) disease, in which autoreactive B cells and CD8+ T cells play a dominant role in its pathophysiology. In MS, diverse autoantibodies against the lipid-protein cofactors of the myelin sheath have been described, whose pathophysiologic role has not been fully elucidated. We carried out a review to select clinical studies addressing the prevalence of antiphospholipid (aPL) autoantibodies in the so-called MS-like syndrome. The reported prevalence ranged between 2% and 88%, particularly aCL and aß2GPI, with predominant IgM isotype and suggesting worse MS prognosis. Secondarily, an updated summary of current knowledge on the pathophysiological mechanisms and events responsible for these conditions is presented. We draw attention to the clinical relevance of diagnosing isolated neurological APS. Prompt and accurate diagnosis and antiaggregant and anticoagulant treatment of APS could be vital to prevent or at least reduce APS-related morbidity and mortality.

Profiling of Canonical and Non-Traditional Cytokine Levels in Interferon-ß-Treated Relapsing-Remitting-Multiple Sclerosis Patients.

Background: Multiple sclerosis (MS) is a chronic, progressive autoimmune disease of the central nervous system in which inflammation plays a key role in the induction, development, and progression. Most of the MS patients present with relapsing-remitting (RR) form, characterized by flare-ups followed by periods of recovery. Many inflammatory and anti-inflammatory cytokines have been proposed as backers in MS pathogenesis, and the balance between these differing cytokines can regulate MS severity. Interferon (IFN)-ß, a current disease-modifying therapy for MS, has demonstrated beneficial effects in reducing disease severity in MS patients. However, its immunoregulatory and anti-inflammatory actions in MS are not wholly understood. The aim of the study was to define, in clinically stable patients with RR-MS, the serum concentration of several cytokines, canonical or not, and their modulation by IFN-ß therapy. Methods: Relapsing-remitting-MS patients were enrolled and diagnosed according to revised Mc Donald Diagnostic Criteria. A set of cytokines [including non-canonical neurotransmitter acetylcholine (ACh) and adipokines] and B-cell differentiation molecules, as potential biomarkers, were evaluated in 30 non-treated RR-MS patients compared to 30 IFN-ß-treated MS patients and 30 age, gender, and body mass index-matched healthy controls (HC). Results: Naïve MS patients showed significantly higher levels of interleukin (IL)-1ß, IL-12/IL-23p40, IL-18, high-mobility group box protein-1, and IL-18 binding protein (IL-18BP) than MS-treated patients (p < 0.001 for all) and HC (p < 0.01). IFN-ß therapy has significantly downmodulated IL-1ß, IL-12/IL-23p40, IL-18 to normal levels (p < 0.001), whereas it has decreased IL-18BP (p < 0.001). ACh was significantly higher in the IFN-ß-treated than HC and non-treated MS patients (p < 0.001). No significant differences were observed either in adipokines concentration or in B-cell-associated molecules among the three study groups. Conclusion: Although more experimental evidence are required, we speculate that the efficacy of treatment of MS with IFN-ß is mediated, at least in part, by its ability to work on several levels to slow down the disease progression. Proposed actions include the modulation of IL-1-inflammasome axis and modulation of ACh, B-cell activating factor/a proliferation-inducing ligand system, and several adipokines.

Multimarker risk stratification approach at multiple sclerosis onset.

Delay in the diagnosis of multiple sclerosis (MS) stems from the lack of specific clinical and analytical markers to assist in the early diagnosis and prediction of progressive course. We propose a decision-tree model that better defines early at onset MS patients and those with the progressive form by analysing a 12-biomarkers panel in serum and CSF samples of patients with MS, other neurological diseases (OND) and healthy contols. Thus, patients at onset of neurological disease were first classified by serum IL-7 levels <141pg/ml (OR=6.51, p<0.001). Combination of IL-7 and CXCL10 indicated risk for a specific MS clinical form, where IL-7<141 and CXCL10<570pg/ml were associated with the highest risk for PP-MS (OR=22, p=0.01). Unexpectedly, both PP-MS and RR-MS patients shared significantly decreased prototypical biomarkers of inflammation and tissue regeneration in CSF than OND suggesting a defective intrinsic immune response playing a role at the beginning of the disease.

Activation of Blood CD3+CD56+CD8+ T Cells during Pregnancy and Multiple Sclerosis.

A striking common feature of most autoimmune diseases is their female predominance, with at least twice as common among women than men in relapsing-remitting multiple sclerosis (MS), the prevailing MS clinical form with onset at childbearing age. This fact, together with the protective effect on disease activity during pregnancy, when there are many biological changes including high levels of estrogens and progesterone, puts sex hormones under the spotlight. The role of natural killer (NK) and NKT cells in MS disease beginning and course is still to be elucidated. The uterine NK (uNK) cells are the most predominant immune population in early pregnancy, and the number and function of uNK cells infiltrating the endometrium are sex-hormones' dependent. However, there is controversy on the role of estrogen or progesterone on circulating NK (CD56dim and CD56bright) and NKT cells' subsets. Here, we show a significantly increased activation of CD3+CD56+CD8+ cells in pregnant MS women (MSP) compared with non-pregnant MS women (NPMS) (p < 0.001) and even with respect to healthy pregnant women (HP, p < 0.001), remaining increased even after delivery. The dynamics of expression of early activation marker CD69 on CD3+CD56+CD8+ cells showed a progressive statistically significant increase along the gestation trimesters (T) and at postpartum (PP) with respect to NPMS (1T: p = 0.018; 2T: p = 0.004; 3T: p < 0.001; PP: p = 0.001). In addition, early activation expression of CD69 on CD3+CD56+CD8+ cells was higher in MSP than HP in the first two trimesters of gestation (p = 0.004 and p = 0.015, respectively). NPMS showed significantly increased cytotoxic/regulatory NK ratio compared with healthy controls (p < 0.001). On the other hand, gender studies showed no differences between MS women and men in NK and CD3+CD56+CD8+ cells' subsets. Our findings may add on the understanding of the regulatory axis in MS during pregnancy. Further studies on specific CD8+ NKT cells function and their role in pregnancy beneficial effects on MS are warranted to move forward more effective MS treatments.

Close Encounters of the First Kind: Innate Sensors and Multiple Sclerosis.

Although autoimmune diseases by definition imply adaptive immune system pathologies, growing evidence points to the relevance of innate receptors in modulating the initiation and progression of the autoreactive response. Multiple sclerosis (MS) is a chronic autoimmune disease characterised by central nervous system (CNS) demyelination, inflammation and axonal damage, in which the role of several pathogens such as herpes viruses have long been described as potential triggers. Encounters of these pathogens with altered innate receptors in susceptible individuals might drive pathological autoreactivity and inflammation, overcoming tolerance and causing subsequent CNS damage. In particular, functional and genetic studies reveal that Toll-like receptor (TLR) 2 and the Nod-like receptor (NLR) P3 could be involved in MS pathogenesis, whereas TLR3, the triggering receptor expressed on myeloid cells (TREM)-2 and the C-type lectin receptors (CLRs) MBL and MASP-3 would have a putative protective role. A better understanding of these interactions will provide important insights into the aetiopathogenesis of MS and could help design potential targets for novel therapies.

Plasma biomarkers discriminate clinical forms of multiple sclerosis.

Multiple sclerosis, the most common cause of neurological disability in young population after trauma, represents a significant public health burden. Current challenges associated with management of multiple sclerosis (MS) patients stem from the lack of biomarkers that might enable stratification of the different clinical forms of MS and thus prompt treatment for those patients with progressive MS, for whom there is currently no therapy available. In the present work we analyzed a set of thirty different plasma cytokines, chemokines and growth factors present in circulation of 129 MS patients with different clinical forms (relapsing remitting, secondary progressive and primary progressive MS) and 53 healthy controls, across two independent cohorts. The set of plasma analytes was quantified with Luminex xMAP technology and their predictive power regarding clinical outcome was evaluated both individually using ROC curves and in combination using logistic regression analysis. Our results from two independent cohorts of MS patients demonstrate that the divergent clinical and histology-based MS forms are associated with distinct profiles of circulating plasma protein biomarkers, with distinct signatures being composed of chemokines and growth/angiogenic factors. With this work, we propose that an evaluation of a set of 4 circulating biomarkers (HGF, Eotaxin/CCL11, EGF and MIP-1ß/CCL4) in MS patients might serve as an effective tool in the diagnosis and more personalized therapeutic targeting of MS patients.