Immunologic Response

Updated by Rohin Gawdi on 5/03/2020.

Summary: Immunologic Response

• Early stage of symptoms are accompanied by mild lymphopenia

  • Loss of B-cells can cause a loss of antibody production

• Patients that experience acute pneumonia tend to have lower lymphocyte counts than patients that recover.

• Patients with multifunctional CD4+ T-cells (expressing two of IFN-gamma, TNF-a, or IL-2) and exhausted CD8+ T-cells (expressing PD-1, CTLA-4, and TIGIT) are less likely to experience worsened symptoms.

  • This is unusual for coronavirus infections; suggesting unique pathogenesis for SARS-CoV-2

• HLA subtypes may confer susceptibility or relative immunity to severe COVID-19, but more research is needed to evaluate this

Literature Review:

During the first 7 days of symptom presentation, mild lymphopenia is noted. It is suspected that B-cell lymphopenia occurs early in disease progression, adversely affecting antibody production. Patients who experience aggressive decompensation, referred to as the “second attack”, tend to have more significant lymphopenia compared to patients whose conditions do not aggravate. In patients who progress to severe disease, lymphocyte count continues to decrease significantly (13).

Not only do T-cell counts vary significantly between severely and mildly ill patients, but T-cell functionality plays a role in vulnerability to severe illness. CD4+ cells express functional molecules IFN-gamma, TNF-a, and IL-2. So-called multifunctional CD4+ T-cells express two or more of these molecules, while non-functional CD4+ T-cells express none of these molecules (IFN-gamma-, TNF-a-, IL-2-). In a 2008 study from Li et al. analyzing SARS-CoV proportion of multi-functional and non-functional CD4+ T-cells, patients with more severe SARS infection presented with far more multi-functional T-cells than those with milder infections (18). However, in a 2020 study from Zheng et al. analyzing SARS-CoV-2 infections, multi-functional CD4+ T-cells were actually far less common in severely ill patients than mildly ill patients. Additionally, higher concentrations of non-functional CD4+ T cells were significantly more common in severe patients than mild and healthy patients. This result suggests that SARS-CoV-2 infections may possess a pathogenesis unique among CoV species. Previous studies on CD4+ cells have shown that multifunctional CD4+ T-cells better control natural HIV-1 infection and correlate with better vaccination outcomes, suggesting that patients with functional damage to their CD4+ cells may be at risk for a more severe COVID-19 clinical course (19). In addition, Zheng et al. also found that CD8+ T-cells of severely ill patients were more likely to express PD-1, CTLA-4, and TIGIT, molecular indicators of CD8+ exhaustion (20). Because blockade of these indicators is critical for CD8+ T-cell ability to maintain lasting immunity and antiviral effects, the presence of these exhaustion molecules may be correlated with increasingly severe COVID-19 symptoms (21). Vulnerability of patients with certain HLA haplotypes to COVID-19 decompensation have also been discussed as a potential means of screening patients as lower or higher risk, though little data currently exists regarding which HLA subtypes confer susceptibility (10).

Summary and Literature Review written by Rohin Gawdi 3/29/2020.