Effects of COVID-19 and vaccination on the human immune system: cases of lymphopenia and autoimmunity

SARS-CoV-2 infection and the antigenic challenge induced by vaccinations against this pathogen elicit a diverse immunological response in humans. A variable immune response is expected during infection, but the ability of SARS-CoV-2 to evade host immunity and induce a deleterious effect on immune-regulating cells, such as macrophages, lymphocytes and natural killer cells make it a complex viral infection to be challenged. Consequently, variable outcomes of infection have been observed. In a small percentage of individuals, such outcomes include the manifestation of lymphocytopenia and autoimmunity. Vaccinations against COVID-19 have also been shown to evoke variance in the immune response in a fraction of vaccinated individuals. Here, we debate such occurrences of immune variance and discuss the underlying pathogenesis of immune deficits and contradictory cases of autoimmune states induced by COVID-19 which have puzzled the scientific community.

Observations of lymphopenia in COVID-19 patients with ominously decreased absolute T-cell counts and elevated levels of proinflammatory cytokines, for example, IFN-γ, IL-6 and IL-8 [1], have puzzled scientists worldwide. Persistently positive antinuclear antibodies 12 months post-COVID in individuals with long-COVID have been reported to be associated with persisting symptoms and inflammation (TNF-α) in a subset of COVID-19 survivors [2]. Though a considerable amount of data has been published on the typical immune response to SARS-CoV-2 infection and COVID-19 vaccination; very little is known about why deviations are observed in an increasing fraction of cases where the immune system is weakened to a remarkable extent. As the Spike (S) protein is known to be the pivotal antigen that incites the production of antibodies and T-killer cells after SARS-CoV-2 infection or vaccination by mRNA vaccines, a variation in the quantitative or qualitative immune response against the S protein and other antigenic components is expected to determine the clinical severity and pattern of COVID-19. Cases where a reduced lymphocyte count occurs and the disease is carried into a chronic symptomatic phase called long-COVID or post-COVID sequelae are puzzling, however. Inadequate viral clearance or persistence of the immune-evading virus can be the underlying cause of long-COVID, but a qualitative immune deficiency in the presence of a normal lymphocyte count in some cases warrants further investigation.

Understanding the complex immune outcomes in COVID-19 would clarify how SARS-CoV-2 interacts with the immune system and makes regulatory cells too weak to target the viral antigen. Manifestations of lymphocytopenia are alarming, and observations of the production of autoimmune antibodies further complicate our understanding of the molecular mechanisms at play in COVID-19 [3]. The spectrum of immune manifestations might be due to the different HLA genotypes which determine the immune response in humans, and differences in disease presentation and hospitalization may be due to some pre-existing susceptibility as a result of unique genetic and clinical profiles. Such lymphotropic effects, as are observed with lymphocytopenia, have resulted in the manifestation of certain opportunistic infections in patients with post-COVID infection states. The Epstein–Barr virus, herpes simplex virus and certain strains of other viruses have been detected in patients with COVID-19 and long-COVID with lymphocytopenia [4]. Reports of extensive fungal infections following COVID-19 and in long-COVID further describe the possible consequences of lymphopenia as a result of SARS-CoV-2 infection and its persistence in patients. While the emergence of TB cases in patients with reduced lymphocyte counts following or during SARS-CoV-2 infection has not been described, the reactivation of TB during COVID-19 remains a real possibility in countries where tuberculosis (TB) is common, such as in South East Asia [5].

The loss of the checks and balances of the immune system in post-COVID lymphopenia and long-COVID is also a concern for the emergence of various non-communicable diseases like cancer. Reports of the reactivation of tumors such as angioblastoma after the mRNA vaccine booster are disturbing [6], as is the COVID-19 induced depletion of different immune cell types [7]. Similar to tumor viruses, SARS-CoV-2 may accelerate tumor progression by altering the metabolic pathways of tumor cells [8]. Though it is too early to relate COVID-19 induced lymphopenia to malignancies; long-term follow-up of patients suffering persistent lymphopenia following COVID-19 is expected to clarify any association.

Exposure of the S protein in SARS-CoV-2 infection and by current vaccines results in the binding of ACE2 receptors. The downstream effects of this interaction need to be investigated in depth in regulatory immune cells to better understand the loss of immune checks and balances [9]. The binding of the S protein to ACE also deregulates the renin-angiotensin system which may lead to immune deregulation, and in particular, to T-cell lymphodepletion [10]. ACE2-independent pathways to infection of T cells by SARS-CoV-2 could be followed by apoptosis and lymphopenia [11]. Potential targets such as integrins like LFA-1 (essential for the generation of well-structured immunological synapses) may also play a role in the lymphotropic effects of SARS-CoV-2 [12]. The effects of SARS-CoV-2 can be additionally worrisome if the function of monocytes and B cells is affected, as infecting monocytes and macrophages and inducing inflammatory cell death (pyroptosis) can reduce antigen presentation. The loss of this function can lead to unchecked prolonged infections that would normally be prevented by the immune response that follows antigen presentation and subsequent production of IgG-type antibodies and T-killer cells. COVID-19-related immunosuppression could also be explained by post vaccination lymphopenia (and neutropenia) [13,14]. BNT162b1 vaccination in adults is associated with transient lymphopenia in a dose-dependent manner. One study reported decreases in lymphocyte counts after the first dose in 8.3% (1 of 12), 45.5% (5 of 11) and 50.0% (6 of 12) of participants who received 10, 30 and 100 μg of BNT162b1, respectively [15].

The emergence of autoantibodies to human alpha- and beta-adrenergic, muscarinic, ACE and a plethora of other receptors is alarming in COVID-19 [2,3]. It is not known yet whether patients in a lymphopenic state are lymphopenic due to autoimmunity, or whether certain subsets of patients are lymphopenic and the expression of autoantibodies has a separate and unrelated outcome. It is possible the proteins expressed by SARS-CoV-2 could have antigenic similarities with the abovementioned receptors, and thus the IgG produced against the viral protein cross-reacts with proteins expressed in human cells. The mimicry between viral proteins, in particular the S protein and human proteins, can provide a possible explanation for autoimmunity following COVID-19 infection and post-vaccination. While it remains to be established in which viral protein(s) these molecular similarities are located [16]; many examples of the various organs that have been targeted following COVID-19 or vaccination have been reported [17–20]. The production of autoantibodies is expected to magnify the tissue damage often seen in COVID-19 and long-COVID. Patients with long-COVID syndrome have also been reported to be positive for antinuclear antibodies that, in diseases like systemic lupus erythematosus, are known to cause renal failure and cardiac thrombi called ‘vegetation’, which can prove fatal [2,3].

There is an urgent need to not only understand the complexities underlying the immune response in COVID-19 and long-COVID but to investigate how this immune response is different from the one evoked by vaccination for the prevention of COVID-19. The long-term follow-up of patients with COVID-19 and long-COVID, as well as patients who are vaccinated, is important for monitoring immune cell deregulation which can result in the formation of autoantibodies and evoke autoimmunity in susceptible individuals. A qualitative analysis of the functional status of cells involved in immune regulation in vitro is critical to determining the ability of individuals to induce an effective immune response following COVID-19 or in those suffering from long-COVID. Antigenic challenge and stimulation by cytokines is an easy tool to gauge the immunocompetence of individuals who continue to exhibit symptoms after the acute phase of COVID-19. Clues toward the sensitivity of regulatory immune cells for autoimmune disease can also be tested in vitro to identify if some subsets of patients are more prone to develop an immune response to self-antigens after COVID-19 and during long-COVID.