Guglielmo Lucchese

Geographical variations in sex ratio trends over time in multiple sclerosis

Background A female/male (F/M) ratio increase over time in multiple sclerosis (MS) patients was demonstrated in many countries around the world. So far, a direct comparison of sex ratio time-trends among MS populations from different geographical areas was not carried out. Objective In this paper we assessed and compared sex ratio trends, over a 60-year span, in MS populations belonging to different latitudinal areas. Methods Data of a cohort of 15,996 (F = 11,290; M = 4,706) definite MS with birth years ranging from 1930 to 1989 were extracted from the international MSBase registry and the New Zealand MS database. Gender ratios were calculated by six decades based on year of birth and were adjusted for the F/M born-alive ratio derived from the respective national registries of births. Results Adjusted sex ratios showed a significant increase from the first to the last decade in the whole MS sample (from 2.35 to 2.73; p = 0.03) and in the subgroups belonging to the areas between 83° N and 45° N (from 1.93 to 4.55; p<0.0001) and between 45° N to 35° N (from 1.46 to 2.30; p<0.05) latitude, while a sex ratio stability over time was found in the subgroup from areas between 12° S and 55° S latitude. The sex ratio increase mainly affected relapsing-remitting (RR) MS. Conclusions Our results confirm a general sex ratio increase over time in RRMS and also demonstrate a latitudinal gradient of this increase. These findings add useful information for planning case-control studies aimed to explore sex-related factors responsible for MS development.

Peptidology: short amino acid modules in cell biology and immunology

Summary.Short amino acid motifs, either linear sequences or discontinuous amino acid groupings, can interact with specific protein domains, so exerting a central role in cell adhesion, signal transduction, hormone activity, regulation of transcript expression, enzyme activity, and antigen-antibody interaction. Here, we analyze the literature for such critical short amino acid motifs to determine the minimal peptide length involved in biologically important interactions. We report the pentapeptide unit as a common minimal amino acid sequence critically involved in peptide-protein interaction and immune recognition. The present survey may have implications in defining the dimensional module for peptide-based therapeutical approaches such as the development of novel antibiotics, enzyme inhibitors/activators, mimetic agonists/antagonists of neuropeptides, thrombolitic agents, specific anti-viral agents, etc. In such a therapeutical context, it is of considerable interest that low molecular weight peptides can easily cross biological barriers, are less susceptible to protease attacks, and can be administered at high concentrations. In addition, small peptides are a rational target for strategies aimed at antigen-specific immunotherapeutical intervention. As an example, specific short peptide fragments might be used to elicit antibodies capable of reacting with the full-length proteins containing the peptide fragment’s amino acid sequence, so abolishing the risk of cross-reactivity.

Impact of Natalizumab on Cognitive Performances and Fatigue in Relapsing Multiple Sclerosis: A Prospective, Open-Label, Two Years Observational Study

Background and Objectives Natalizumab reduces the relapse rate and magnetic resonance imaging activity in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). So far the influence of natalizumab on cognitive functions and fatigue in MS remains uncertain. The aim of this prospective, open-label, observational study was to evaluate the possible effects of natalizumab on cognition and fatigue measures in RRMS patients treated for up to two years. Methods Cognitive performances were examined by the Raos Brief Repeatable Battery (BRB), the Stroop test (ST) and the Cognitive Impairment Index (CII), every 12 months. Patients who failed in at least 3 tests of the BRB and the ST were classified as cognitively impaired (CI). Fatigue Severity Scale (FSS) was administered every 12 months to assess patients self-reported fatigue. One hundred and 53 patients completed 1 and 2 year-natalizumab treatment, respectively. Results After 1 year of treatment the percentage of CI patients decreased from 29% (29/100) at baseline to 19% (19/100) (p = 0.031) and the mean baseline values of CII (13.52±6.85) and FSS (4.01±1.63) scores were significantly reduced (10.48±7.12, p<0.0001 and 3.61±1.56, p = 0.008). These significant effects were confirmed in the subgroup of patients treated up to two years. Conclusions These results demonstrate that a short-term NTZ treatment may significantly improve cognitive performances and fatigue in RRMS patients.

Zika virus and autoimmunity: From microcephaly to Guillain-Barré syndrome, and beyond

Zika virus (ZIKV) infection during pregnancy may be linked to fetal neurological complications that include brain damage and microcephaly. How the viral infection relates to fetal brain malformations is unknown. This study analyzes ZIKV polyprotein for peptide sharing with human proteins that, when altered, associate with microcephaly and brain calcifications. Results highlight a vast viral versus human peptide commonality that, in particular, involves centriolar and centrosomal components canonically cataloged as microcephaly proteins, i.e., C2CD3, CASC5, CP131, GCP4, KIF2A, STIL, and TBG. Likewise, a search for ZIKV peptide occurrences in human proteins linked to Guillain-Barré-like syndromes also show a high, unexpected level of peptide sharing. Of note, further analyses using the Immune Epitope DataBase (IEDB) resource show that many of the shared peptides are endowed with immunological potential. The data indicate that immune reactions following ZIKV infection might be a considerable source of crossreactions with brain-specific proteins and might contribute to the ZIKV-associated neuropathologic sequelae.

Massive peptide sharing between viral and human proteomes

Abstract Thirty viral proteomes were examined for amino acid sequence similarity to the human proteome, and, in parallel, a control of 30 sets of human proteins was analyzed for internal human overlapping. We find that all of the analyzed 30 viral proteomes, independently of their structural or pathogenic characteristics, present a high number of pentapeptide overlaps to the human proteome. Among the examined viruses, human T-lymphotropic virus 1, Rubella virus, and hepatitis C virus present the highest number of viral overlaps to the human proteome. The widespread and ample distribution of viral amino acid sequences through the human proteome indicates that viral and human proteins are formed of common peptide backbone units and suggests a fluid compositional chimerism in phylogenetic entities canonically classified distantly as viruses and Homo sapiens. Importantly, the massive viral to human peptide overlapping calls into question the possibility of a direct causal association between virus–host sharing of amino acid sequences and incitement to autoimmune reactions through molecular recognition of common motifs.

Non-self-discrimination as a driving concept in the identification of an immunodominant HMW-MAA epitopic peptide sequence by autoantibodies from melanoma cancer patients

We analyzed the sera of patients with melanoma to define the human humoral autoantibody profile towards HMW‐MAA. Computational proteome scanning using the non‐self‐discrimination principle as a guide led to the individuation of the low‐similarity HMW‐MAA781–789RATVWMLRL peptide fragment as an immunodominant B‐cell epitope. Linear B‐cell determinant individuation was experimentally validated by dot blot immunoassay and NMR spectroscopy analysis. Regulation of physiologic self‐reactivity by the non‐self‐discrimination principle is discussed.

Natural History of Multiple Sclerosis: Have Available Therapies Impacted Long-Term Prognosis?

Since the mid-1990s several disease-modifying drugs (DMDs), such as β-interferons and glatiramer acetate, have become available to treat patients with relapse-remitting multiple sclerosis (MS). These therapies have known short- and medium-term benefit in reducing relapses, disability progression, and accrual of new inflammatory lesions. However, the short duration of the randomized pivotal MS trials have provided little to no information about benefit from such treatment over periods of extended (>5 years) use. Whether DMDs may significantly alter the development of long-term disability remains uncertain, thus it remains challenging how to best approach the issue of long-term benefits from these treatments.

Proposing low-similarity peptide vaccines against Mycobacterium tuberculosis.

Using the currently available proteome databases and based on the concept that a rare sequence is a potential epitope, epitopic sequences derived from Mycobacterium tuberculosis were examined for similarity score to the proteins of the host in which the epitopes were defined. We found that: (i) most of the bacterial linear determinants had peptide fragment(s) that were rarely found in the host proteins and (ii) the relationship between low similarity and epitope definition appears potentially applicable to T-cell determinants. The data confirmed the hypothesis that low-sequence similarity shapes or determines the epitope definition at the molecular level and provides a potential tool for designing new approaches to prevent, diagnose, and treat tuberculosis and other infectious diseases.

Proteome-guided search for influenza A B-cell epitopes.

The influenza A linear peptide epitopes recognized by murine antibodies, and currently cataloged at http://www.immuneepitope.org, were examined for the identity score to the host mouse proteome. It was found that almost all of the linear viral determinants are (or contain) regions formed by pentapeptide fragments with no or only very low similarity to the murine proteins. The present study adds to previous reports in suggesting a main role of amino acid sequence similarity in the modulation and definition of the B-cell epitope repertoire, inspiring innovative vaccine approaches able to avoid cross-reactive autoimmune collateral phenomena, and addressing future research in the study of immunity against the influenza A virus and infectious diseases in general.

Sequence uniqueness and sequence variability as modulating factors of human anti-HCV humoral immune response

We recently compared the HCV polyprotein to the human proteome in order to test whether amino acid sequences unique to the virus could represent immunodominant epitopic determinants of the human humoral immune response against HCV. We identified a relatively limited number of HCV fragments with no/low similarity to the human host that represented exclusive HCV motifs. In this study, the peptides corresponding to low/zero similarity sequences were synthesized and assayed with HCV-infected sera. With different patterns, the synthetic HCV peptides corresponding to low/zero similarity sequences were found to be immunoreactive. In particular, the HCV E1 (315–323) HRMAWDMMM, HCV E2/NS1 (547–555) NWFGCTWMN, and HCV NS5 (2638–2646) YDTRCFDST sequences were immunodominant in the HCV-infected cohort under study. These three peptides correspond to sequences that are endowed with low-similarity to the human proteome, are highly conserved among various HCV strains, and have, potentially, a scarce susceptibility to proteolytic attacks. These data may be of help in defining the multiple factors which concur in the modulation of the human immune response against HCV, eventually providing information for the design of effective anti-HCV vaccines.