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SARS-CoV2 virus affects the immune system at multiple sites.1 Severe cases with a cytokine storm show massive defects of all T cell subsets with lymphopenia. B cells are rather hyper-reactive, suggesting defective regulation from T cells and patients with severe forms produce higher levels of antivirus antibodies.2 However, the production of high affinity and protective antibodies requires a fine tuning of the interactions between viral-specific T and B cells. Defects of such regulation can lead to changes in immunoglobulin (Ig) production, with reduction of their protective properties, and induction of autoreactive and possibly pathogenic antibodies through tolerance loss. Serum protein electrophoresis is a simple way to look at Ig heterogeneity. Profiles can show polyclonal hypergammaglobulinaemia, oligoclonality with several small spikes or monoclonality with single M-spike.
From 3 March to 30 April 2020, 136 patients tested PCR-positive for SARS-CoV2 and 258 negative patients admitted at the same time for another diagnosis and systematically tested for SARS-CoV2, were included. All had serum protein electrophoresis at entry. C reactive protein (CRP) and neutrophil lymphocyte ratio were used as markers of severity.3 PCR-positive patients were older and 51/136 (37.5%) in intensive care units (table 1).
Comparison of electrophoresis patterns showed differences. As expected,there was an increased frequency of inflammatory profiles (83/136, 61% in positive vs 116/258, 45% in negative patients, p=0.003). The key difference was the high frequency of oligoclonal profiles with a few small spikes, in 29/136, 21.3% in positive vs 6/258, 2.3% negative patients, p<0.0001. There was no difference for the presence of a single monoclonal M-spike (all but two in SARS-CoV2 patients were already known). Frequency of increased (11% for positive vs 13.6% for negative patients, p=0.53) or decreased (8.8% vs 14%, respectively, p=0.15) gammaglobulin concentrations was not different between the two groups.
Such 10-fold-increase of oligoclonality could results from the virus, inflammation or both. In the 136 PCR-positive patients, CRP was not different between patients with and without oligoclonality (48±52 mg/L vs 61±69 mg/L, p=0.65), as for WCC count (8.3±3.6 10ˆ9/L vs 7.8±8.4 10ˆ9/L, p=0.13). The neutrophil/lymphocyte ratio was modestly higher in patients with oligoclonal profiles (5.9±4.3 vs 4.2±4.3, p=0.08), with higher neutrophil count (5.8±2.7 vs 4.5±2.6 G/L, p=0.03 g/L). Frequency of oligoclonal profiles in positive patients admitted to intensive care units was not different than in those that did not require such admission (19.6% vs 22.3%, p=0.8).
These results are in favour of defects in the regulation of Ig synthesis during COVID-19, and suggest a contribution from both the virus and inflammation.3 4 Similar increase of Ig oligoclonality is commonly seen in autoimmunity, typically in Sjogren’s syndrome, but also in other infections.5 Such profile in COVID-19 further indicates defects in the crosstalk between T and B cells. They add to the concerns regarding the quality of the immune response. In COVID-19, various autoantibodies have been described, such asanti-phospholipid antibodies that can contribute to massive immune-mediated thrombosis and emboli.6 Long-term studies are needed to evaluate the duration and pathogenicity of these changes. These results with possible induction of autoreactivity by the virus are also important to consider for current vaccine development.
Handling editor Josef S Smolen
Contributors MK-S: analysis of results and writing. PM: concept, writing and submission.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Ethics approval The protocol was approved by the Ethics Committee of the Hospitals of Lyon for the protection of individuals participating in biomedical research under the number AC-2016-2729.
Provenance and peer review Not commissioned; externally peer reviewed.