Rheumatoid arthritis (RA) is an autoimmune disease that involves multiple joints bilaterally. It is characterized by an inflammation of the tendon (tenosynovitis) resulting in both cartilage destruction and bone erosion. While until the 1990s RA frequently resulted in disability, inability to work, and increased mortality, newer treatment options have made RA a manageable disease. Here, great progress has been made in the development of disease-modifying anti-rheumatic drugs (DMARDs) which target inflammation and thereby prevent further joint damage. The available DMARDs are subdivided into (1) conventional synthetic DMARDs (methotrexate, hydrochloroquine, and sulfadiazine), (2) targeted synthetic DMARDs (pan-JAK- and JAK1/2-inhibitors), and (3) biologic DMARDs (tumor necrosis factor (TNF)-α inhibitors, TNF-receptor (R) inhibitors, IL-6 inhibitors, IL-6R inhibitors, B cell depleting antibodies, and inhibitors of co-stimulatory molecules). While DMARDs have repeatedly demonstrated the potential to greatly improve disease symptoms and prevent disease progression in RA patients, they are associated with considerable side-effects and high financial costs. This review summarizes our current understanding of the underlying pathomechanism, diagnosis of RA, as well as the mode of action, clinical benefits, and side-effects of the currently available DMARDs.

Since the approval of the first monoclonal antibody (mAb) in 1986, a huge effort has been made to guarantee safety and efficacy of therapeutic mAbs. As of July 2021, 118 mAbs are approved for the European market for a broad range of clinical indications. In order to ensure clinical efficacy and safety aspects, (pre-)clinical experimental approaches evaluate the respective modes of action (MoA). In addition to antigen-specificity including binding affinity and -avidity, MoA comprise Fc-mediated effector functions such as antibody dependent cellular cytotoxicity (ADCC) and the closely related antibody dependent cellular phagocytosis (ADCP). For this reason, a variety of cell-based assays have been established investigating effector functions of therapeutic mAbs with different effector/target-cell combinations and several readouts including Fcγ receptor (FcγR)-mediated lysis, fluorescence, or luminescence. Optimized FcγR-mediated effector functions regarding clinical safety and efficacy are addressed with modification strategies such as point mutations, altered glycosylation patterns, combination of different Fc subclasses (cross isotypes), and Fc-truncation of the mAb. These strategies opened the field for a next generation of therapeutic mAbs. In conclusion, it is of major importance to consider FcγR-mediated effector functions for the efficacy of therapeutic mAbs.

The exact role of innate immune cells upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their contribution to the formation of the corona virus-induced disease (COVID)-19 associated cytokine storm is not yet fully understood. We show that human in vitro differentiated myeloid dendritic cells (mDC) as well as M1 and M2 macrophages are susceptible to infection with SARS-CoV-2 but are not productively infected. Furthermore, infected mDC, M1-, and M2 macrophages show only slight changes in their activation status. Surprisingly, none of the infected innate immune cells produced the pro-inflammatory cytokines interleukin (IL)−6, tumor necrosis factor (TNF)-α, or interferon (IFN)−α. Moreover, even in co-infection experiments using different stimuli, as well as non-influenza (non-flu) or influenza A (flu) viruses, only very minor IL-6 production was induced. In summary, we conclude that mDC and macrophages are unlikely the source of the first wave of cytokines upon infection with SARS-CoV-2.

Severe Influenza A virus (IAV) infections are accompanied by a cytokine storm with type I interferon (IFN) as the main driver. Besides epithelial cells, alveolar macrophages and infiltrating dendritic cells are target cells for IAV. IAV are classified into different strains, defined by their major surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). So far, 19 HA subtypes and 11 NA subtypes are known. However, it is not well understood, why infection with certain IAV strains results in a cytokine storm with severe outcomes, while other IAV strains only cause mild infections.In order to address this question, we investigated six seasonal and five highly pathogenic avian IAV (HPAIV) strains using primary human ex vivo isolated plasmacytoid dendritic cells (pDC), as well as in vitro differentiated myeloid dendritic cells (mDC) and macrophages (type M1 and M2). Our data reveal that IFN-α production by mDC and macrophages but not by pDC is dependent on productive infection with the respective IAV strain. In contrast to IFN-α production in pDCs, IFN-α production by mDC as well as M1 and M2 macrophages is mainly induced by HPAIV strains, indicating that other immune cells apart from pDC might have an impact on induction of type I interferon as the main driver of the cytokine storm in the patients and the severity of the associated disease. Our findings may provide insights into the viral tropism and host response upon infection with different IAV strains and improve the understanding of the accompanied pathogenesis.

The impact of Mycoplasma contaminations on in vitro test systems has been extensively discussed and in vitro studies have demonstrated various effects on the physiology of the contaminated cell line. Thus far, little is known about the effect of biologically active substances, such as viruses produced in contaminated cell lines on primary immune cells. Therefore, the aim of the present study was to pinpoint the impact of Mycoplasma contamination on human innate immune cells. To address this, myeloid dendritic cells (mDC) and two types of macrophages (type M1 and M2) were in vitro differentiated from healthy donors and treated with different volumes of cell‐culture supernatant from Mycoplasma ‐contaminated VeroE6 cells (SN(M)). Depending on the cell type, Mycoplasma contamination mediated a decrease in viability and the pre‐activation of the immune cells. Surprisingly, small amounts of SN(M) were sufficient to induce the secretion of massive amounts of pro‐inflammatory interleukin (IL)−6 and, to a lesser extent, tumor necrosis factor (TNF)‐α and interleukin (IL)−10. Moreover, SN(M) co‐stimulation of cells treated with a variety of toll‐like receptor (TLR) ligands and different RNA‐encoded viruses differentially altered their activation status, depending on the analyzed markers, cell types, and stimuli. Furthermore, SN(M) co‐treatment strongly influenced the induced cytokine profile of mDC as well as M1 and M2 macrophages upon treatment with various stimuli, especially upon viral infection. In line with this, a batch of SARS‐CoV‐2 produced in Mycoplasma ‐contaminated VeroE6 cells induced high levels of IL‐6 and TNF‐α while treatment with the non‐contaminated virus stock did not result in expression of cytokines. Our data indicate that Mycoplasma contamination has a major impact on the experimental outcome of infection experiments using human immune cells and therefore can result in misinterpretation of experimental data.