Humoral immune mechanisms involved in protective and pathological immunity during COVID-19

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 is associated with excessive inflammation, as a main reason for severe condition and death. Increased inflammatory cytokines and humoral response to SARS-CoV-2 correlate with COVID-19 immunity and pathogenesis. Importantly, the levels of pro-inflammatory cytokines that increase profoundly in systemic circulation appear as part of the clinical pictures of two overlapping conditions, sepsis and the hemophagocytic syndromes. Both conditions can develop lethal inflammatory responses that lead to tissue damage, however, in many patients hemophagocytic lymphohistiocytosis (HLH) can be differentiated from sepsis. This is a key issue because the life-saving aggressive immunosuppressive treatment, required in the HLH therapy, is absent in sepsis guidelines. This paper aims to describe the pathophysiology and clinical relevance of these distinct entities in the course of COVID-19 that resemble sepsis and further highlights two effector arms of the humoral immune response (inflammatory cytokine and immunoglobulin production) during COVID-19 infection.

Keywords: 2019 novel coronavirus disease (COVID-19); Antibody response; Hemophagocytic lymphohistiocytosis (HLH); Sepsis; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Fig. 1

Schematic diagram of the pathological effects of immune system cytokines in COVID-19. During the disease caused by SARS-CoV-2, activated monocytes and macrophages produce various cytokines such as IL-1, IL-6, and TNFα which can cause cytokine storm and multiorgan damage. IL-6 also can induce liver cells to synthesize acute phase proteins and is associated with low albumin and transferrin concentrations. In addition, IL-12, produced by monocyte/macrophage, dendritic cell and B cells, may induce NK and T cells to secrete IFN-γ which in turn stimulates IL-12 production in a positive feedback loop. SAA; serum amyloid A, CRP; C reactive protein, Th; helper T cell, IL-; interleukin-, TNF-α; tumor necrosis factor alpha, GM-CSF; granulocyte–macrophage colony-stimulating factor, MCP-1; monocyte chemoattractant protein1, IP-10; Interferon-Inducible Protein 10, IFNγ; interferon γ protein.

Fig. 2

Specific macrophage-monocyte lineage cells surrounding alveoli that cause local pulmonary inflammation after SARS-CoV-2 infection or COVID-19 disease. The composition of immune cells localized to the lung differs across patients ranging from mild to severe. The pathological investigation in mild cases of COVID-19 reveals massive infiltration of alveolar macrophages, while in the severely injured lung the predominant macrophage lineage is inflammatory FCN1 + macrophages, that associates with monocyte-derived macrophages. A unique monocyte subset called as “severe stage-specific monocyte” exists only in severe stage patients with COVID-19.

Fig. 3

Antibody response associates with viral load and shedding of patients with COVID-19 infection. In the early infection the specific antibody responses against SARS-CoV-2 is mainly the IgM antibody response that is correlated to higher viral clearance whereas following seroconversion or in the individuals who produce IgG earlier than IgM, the higher viral load and longer duration of viral shedding has been detected.