The current pandemic coronavirus, SARS-CoV-2, is a global health emergency because of its highly contagious nature, the great number of patients requiring intensive care therapy, and the high fatality rate. In the absence of specific antiviral drugs, passive prophylaxis, or a vaccine, the treatment aim in these patients is to prevent the potent virus-induced inflammatory stimuli from leading to the acute respiratory distress syndrome (ARDS), which has a severe prognosis. Here, the mechanism of action and the rationale for employing immunological strategies, which range from traditional chemically synthesized drugs, anti-cytokine antibodies, human immunoglobulin for intravenous use, to vaccines, are reviewed.

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SARS-CoV-2 infection complicated by inflammatory syndrome. Could high-dose human immunoglobulin for intravenous use (IVIG) be beneficial?

Antigen-mimicking peptide (mimotope)-based vaccines are one of the most promising forms of active-immunotherapy. The main drawback of this approach is that it induces antibodies that react poorly with the nominal antigen. The aim of this study was to investigate the molecular basis underlying the weak antibody response induced against the naïve protein after peptide vaccination. For this purpose, we analyzed the fine specificity of monoclonal antibodies (mAb) elicited with a 13-mer linear peptide, complementary to theantigen-combining site of the anti-CD20 mAb, Rituximab, in BALB/c mice. Anti-peptide mAb competed with Rituximab for peptide binding. Even so, they recognized a different antigenic motif from the one recognized by Rituximab. This explains their lack of reactivity with membrane (naïve) CD20. These data indicate that even on a short peptide the immunogenic and antigenic motifs may be different. These findings highlight an additional mechanism for epitope spreading and should be taken into account when designing peptides for vaccine purposes.

Aquaporin-4 (AQP4) is the CNS water channel organized into well-ordered protein aggregates called Orthogonal Arrays of Particles (OAPs). Neuromyelitis Optica (NMO) is an autoimmune disease caused by anti-OAP autoantibodies (AQP4-IgG). Molecular Dynamics (MD) simulations have identified an H-bond between L53 and T56 as the key for AQP4 epitope and therefore of potential interest for drug design in NMO field. In the present study, we have experimentally tested this MD-prediction using the classic mutagenesis approach. We substituted T56 with V56 and tested this mutant for AQP4 aggregates and AQP4-IgG binding. gSTED super-resolution microscopy showed that the mutation does not affect AQP4 aggregate dimension; immunofluorescence and cytofluorimetric analysis demonstrated its unaltered AQP4-IgG binding, therefore invalidating the MD-prediction. We later investigated whether AQP4, expressed in Sf9 insect and HEK-293F cells, is able to correctly aggregate before and after the purification steps usually applied to obtain AQP4 crystal. The results demonstrated that AQP4-IgG recognizes AQP4 expressed in Sf9 and HEK-293F cells by immunofluorescence even though BN-PAGE analysis showed that AQP4 forms smaller aggregates when expressed in insect cells compared to mammalian cell lines. Notably, after AQP4 purification, from both insect and HEK-293F cells, no aggregates are detectable by BN-PAGE and AQP4-IgG binding is impaired in sandwich ELISA assays. All together these results indicate that 1) the MD prediction under analysis is not supported by experimental data and 2) the procedure to obtain AQP4 crystals might affect its native architecture and, as a consequence, MD simulations. In conclusion, given the complex nature of the AQP4 epitope, MD might not be the suitable for molecular medicine advances in NMO.

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Spondyloarthritis (SpA) is a group of inflammatory rheumatic diseases characterized by common clinical features, such as inflammatory enthesitis, arthritis and/or back pain. SpA is strongly associated with human leukocyte antigen (HLA) class I allotype B27. Ankylosing spondylitis has historically been the SpA subgroup with one of the strongest, best-proven associations with HLA-B27. The remaining SpA subgroups, namely psoriatic arthritis (PsA), inflammatory bowel diseases-associated arthritis/spondylitis, reactive arthritis, and undifferentiated SpA (uSpA), have also been associated with HLA allotypes other than HLA-B27. In this retrospective study, we analyzed the association between the HLA class I and II haplotypes and the susceptibility to enthesitis and/or arthritis (E/A). Special attention was paid to E/A responding to disease-modifying antirheumatic drugs (DMARDs) not fulfilling ASAS classification criteria (ASAS−), as compared to ASAS+ forms including PsA and uSpA. The whole E/A group showed significant independent associations with HLA-A28(68), B27, Cw3, Cw12, and DQ1; taken singly, PsA was associated with HLA-B27 and DQ1, uSpA with HLA-B16(38,39) and B27, and E/A ASAS− with HLA-A28(68), Cw8, and Cw12. This study identified novel risk HLA allotypes for different SpA subgroups in an Italian population. HLA typing could aid the diagnosis and treatment of E/A subgroups, including DMARDS-responsive forms not fulfilling ASAS classification criteria.