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Certain anti-chemokine autoantibodies are associated with favorable outcomes in COVID-19 convalescents

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is a systemic multiple-organ disease characterized by a broad spectrum of clinical manifestations. The consortium of researchers, led by authors from Switzerland, evaluated the presence of anti-chemokine autoantibodies in COVID-19 convalescents.

More than three years after the global COVID-19 pandemic, it is clear that infection with SARS-CoV-2 can lead to a new disease called long-COVID-19 or post-acute COVID-19 syndrome. It is more common in hospitalization survivors, but, even those who have experienced mild acute COVID-19 have a wide range of frequent, persistent, and disabling symptoms. The mechanisms underlying long COVID and the differences in its manifestation are poorly understood.

The S protein appears to be a major pathogenic factor that contributes to the unique pathogenesis of SARS-CoV-2. The S protein is a glycosylated homotrimer with each monomer composed of subunits S1 and S2, separated by host cell proteases. The S1 domain comprises the N-terminal domain (NTD), the receptor binding domain (RBD) with a receptor binding motif (RBM), and two C-terminal domains. The RBD in the S1 subunit recognizes human host cell angiotensin-converting enzyme 2 receptor (ACE2). 

Chemokines are a class of chemotactic cytokines with a key role in directing the migrating and positioning of immune cells within the human body. Acute COVID-19 is characterized by high expression of certain chemokines, which recruit neutrophils and monocytes to sites of infection. These chemokines are significant for the pathophysiological processes of COVID-19 by sustaining inflammation and causing collateral tissue damage. The variety of anti-chemokine antibodies, induced upon infection, may modulate the inflammatory response, the manifestation of disease, and the persistence of COVID symptoms.

 

About the study

The researchers examined the presence of anti-chemokine antibodies in plasma samples collected from 43 COVID-19 convalescents divided into three independent cohorts from Lugano, Milano, or Zurich, six and twelve months after the onset of acute infection. The study also included 23 healthy controls. They were uninfected, confirmed by a negative serologic test.

Twelve months after the infection with SARS-CoV-2, the Lugano cohort was asked to answer a questionnaire about self-reported symptoms of long-COVID. 65% of participants reported at least one persistent symptom. The average number of long-term symptoms was 3.3. Symptoms of long COVID were more frequently reported in formerly hospitalized (72.7%) than in outpatient (47.4%) convalescents. 

The authors used the enzyme-linked immunosorbent assay, and pseudovirus-based neutralization assay to assess the binding and neutralizing capacity of anti-SARS-CoV-2 antibodies in plasma samples. The results showed that antibodies against RBD of SARS-CoV-2 S protein and values of half-maximal SARS-CoV-2 neutralizing titers (NT50) were significantly higher in previously hospitalized convalescents than in outpatient convalescents, as well as in men than in women. The levels of anti-SARS-CoV-2-RBD IgG antibodies and NT50 values did not correlate with concentrations of antibodies against COVID-19 signature chemokines (CCL19, CCL22, and CXCL17), or with the sum of all chemokine IgG reactivities.

I Anti-chemokine autoantibodies in COVID-19 convalescents

The authors used plasma samples from the acute phase of infection to investigate the kinetics of autoantibodies against certain chemokines. They noted that antibodies against COVID-19 signature chemokines (CCL19, CCL22, and CXCL17), which distinguished COVID-19 convalescents from healthy controls, were different from those associated with COVID-19 severity signature (CXCL5, CXCL8, and CCL25). In the Milan cohort, concentrations of autoantibodies against COVID-19 signature chemokines (CCL19, CCL22, and CXCL17) during the acute phase were higher than in healthy controls. In the Lugano cohort, concentrations of autoantibodies against CCL19 (but not to CCL22 or CXCL17) during the acute phase were higher than in healthy controls, and they continued to rise until twelve months.

Temporal dynamics of anti-chemokine autoantibodies at six and twelve months after the onset of COVID-19 showed that autoantibodies to CCL19, CCL8, CCL13, CCL16, CXCL7, and CX3CL1 significantly increased, regardless of the vaccination status. Autoantibodies to CXCL17 remained generally stable. The autoantibodies to CCL22 displayed variable kinetics twelve months after the infection, compared to those observed after six months.

In convalescents from the Milan cohort, the concentrations of several chemokines significantly increased both during acute disease (CCL2, CCL3, CCL4, CCL19, CCL21, CCL22, CCL25, CXCL2, CXCL8, CXCL9, CXCL10, CXCL13, and CXCL16) and after seven months (CCL19, CCL21, CCL22, CXCL2, CXCL8, CXCL10, CXCL13, and CXCL16). There was no correlation between concentrations of chemokines and their corresponding autoantibodies in the acute phase and seven months after the infection.

In twelve individuals from the Lugano cohort, the concentrations of CCL3 and CCL4 chemokines were elevated six months after the infection, but, there was no increase in autoantibodies against CCL3 and CCL4. Some chemokines rapidly increased and persisted in plasma for at least six months after the infection, but, there was no correlation between chemokine levels and their corresponding autoantibodies.

II Anti-chemokine autoantibodies and severity of infection

The researchers further examined the connection between the severity of infection and the presence of anti-chemokine autoantibodies. Outpatient convalescents from the Lugano cohort had a broader pattern and a higher overall level of anti-chemokine autoantibodies than hospitalized convalescents six months after the onset of COVID-19. Compared to hospitalized convalescents, outpatient convalescents also had higher levels of antibodies against the chemokines associated with COVID-19 severity signature (CXCL5, CXCL8, and CCL25), and this was not related to therapy given during hospitalization. Compared to healthy controls, outpatient convalescents had higher concentrations of autoantibodies against eight chemokines (CXCL8, CCL22, CXCL16, CCL27, CXCL7, CCL20, CX3CL1, and CCL19) and significantly higher cumulative IgG reactivity against the chemokines.

Compared to healthy controls, the convalescents hospitalized during the acute phase of COVID-19 had higher concentrations of antibodies only against CCL19 six months after the infection. In hospitalized convalescents, antibodies to CXCL5 and CXCL8 correlated negatively with anti-SARS-CoV-2-RBD IgG. Similar results were found in the Milan and Zurich cohorts. These findings suggest that higher levels of autoantibodies directed against specific chemokines are associated with favorable disease outcomes.

III Anti-chemokine autoantibodies and long-COVID

Researchers also investigated whether specific patterns of anti-chemokine antibodies registered six months after the infection could predict long COVID syndrome. The results showed that convalescents with long COVID had significantly lower cumulative levels and specific patterns of anti-chemokine antibodies, especially outpatients and women, compared to convalescents without long COVID symptoms. 

Convalescents without long COVID had higher concentrations of autoantibodies to CCL21, CXCL13, and CXCL16 than convalescents who developed long COVID syndrome. It seems that autoantibodies against CCL21, CXCL13, and CXCL16 distinguished the group with long COVID from the group without long COVID with high significance. These autoantibodies, therefore, were defined as “long COVID signature”.

The chemokines CCL21, CXCL13, and CXCL16 are important for tissue trafficking and activation of T and B lymphocytes, so, the authors speculated that autoantibodies to these chemokines might positively influence the long-term outcome by antagonizing or modulating the activation, recruitment and retention of T and B lymphocytes.

IV Anti-chemokine autoantibodies in other infections or autoimmune diseases

The authors also evaluated anti-chemokine autoantibodies in patients with other infections or autoimmune disorders, such as chronic HIV-1 infection (n = 24) or infection with Borrelia burgdorferi- Lyme disease (n = 27), ankylosing spondylitis (n = 13), rheumatoid arthritis (n = 13) or Sjögren syndrome (n = 13).

Individuals with chronic HIV-1-infection had significantly increased levels of autoantibodies against 14 chemokines (CCL2, CCL3, CCL4, CCL5, CCL20, CCL21, CCL22, CCL23, CCL27, CCL28, CXCL7, CXCL8, CXCL9 and CXCL12) compared to healthy controls. Plasma from Borrelia-infected individuals was indistinguishable from the healthy controls, except for elevated CXCL14 antibodies in the acute phase. Individuals with ankylosing spondylitis, rheumatoid arthritis, or Sjögren syndrome had higher levels of autoantibodies against four chemokines (CCL4, CCL19, CCL25 and CXCL9) than healthy controls. These findings indicate that different patterns of anti-chemokine autoantibodies distinguished not just different COVID-19 trajectories, but also other infections and autoimmune disorders.

Conclusion

This study showed that antibodies against certain chemokines were omnipresent in COVID-19 convalescents. A higher overall level of anti-chemokine autoantibodies observed in outpatient convalescents than in convalescents hospitalized during acute COVID-19 indicates their association with favorable disease outcomes. Additionally, convalescents who developed long COVID syndrome displayed lower cumulative levels and specific anti-chemokine autoantibody patterns compared to convalescents who were not diagnosed with long COVID. 

This article was published in Nature Immunology.

Journal Reference

Muri J et al. Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course. Nat Immunol 24, 604–611 (2023). (Open Access) https://doi.org/10.1038/s41590-023-01445-w

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