TABLE 1.
Topics to be investigated to fully explain the proposed pathogenic hypotheses of COVID‐19
| Pathogenic hypotheses | Topics to be further investigated |
|---|---|
| Altered coordination between innate and adaptive Immunity 18 |
Factors/mechanisms delaying adaptive immunity. Early alterations in asymptomatic, mild, and severe diseases. The timing and entity of IFN impairment and of NLRP3 inflammasome activation. Macrophages activation and pDC impairment favoring NK dysfunction/exhaustion and trained NK cells response. pDC impairment and reduced antigen presentation to specific T cells. Relationship of delayed adaptive immunity and its relationship with age and other co‐morbidity with chronic inflammations. The circulating proportion of memory versus naïve T and B cells in adults compared with children. Endogeneous corticosteroids, TGF‐β and IL‐10 levels and compensatory hyperactivation of innate immunity and persistence of viral load. |
| Pre‐existing immunity to the virus in unexposed individuals 34 |
Protection given by pre‐existing immunity (memory T and B cells) toward SARS‐CoV2 infection. The permissive HLA haplotypes favoring a quick secondary‐like response. Spectrum of T cell repertoire to CCC epitopes cross‐reacting with SARS‐CoV−2 ones. The mechanism and timing of memory Treg cells impairment. Levels of Ab‐dependent endocytosis in pre‐existing immunity. |
| Super‐antigenic hypothesis 44 , 45 , 46 |
The SAtgs’ sequences of S1 protein. The timing and the degree of SAtg stimulation of T and, subsequently, of B cells. The permissive HLA‐haplotypes favoring polyclonal T cell activation till exhaustion. The interactions between chronically infected cells and polyclonal T cells activated by SAtgs. The association with Treg cell impairment and/or superinfection with other pathogens. |
| Unmasking latent autoimmune/auto‐inflammatory mechanisms 39 , 40 , 42 |
Mechanism(s) and timing of Treg cells dysfunction. Degree of inflammasome activation of infected cells leading to a prevalent type 3 (Th17, Tc17, ILC3) response. Levels of NET‐osis by activated/infected macrophages favoring epitope spreading. Bystander activation of autoreactive T cells. Phenotype and function of autoreactive T and B cells and their expansion during infection. Molecular mimicry between SARS‐CoV2 epitopes and self‐antigens. Fine specificities and pathogenic role of autoantibodies observed in COVID‐19. |
| Prevalence of memory vs naïve T and B cells 68 , 70 |
The circulating proportion of memory versus naïve T and B cells in adults compared with children. CD4+/CD8+ T cell ratio and functional Th subsets in different age ranges. Development of Tfh cells, mB cells and humoral response in different age ranges. TCR repertoire and clonal expansion to novel antigens in different age ranges. Impaired cytotoxicity of CD8+ T and NKT cells in elderly favoring not effective response to new viruses. Trained immunity coupled with pro‐inflammatory cytokines in the elderly. |
Abbreviations: CCC, common cold coronaviruses; pDC, plasmacytoid dendritic cells; IFN, interferon; ILC, innate lymphoid cells; NETs, neutrophils extracellular traps; NK, natural killer; SAtgs, superantigens; Th, T helper; Tc, T cytolytic; Tfh, T follicular helper; Treg, T regulatory.