Background The COVID‐19 vaccine from AstraZeneca (AZD1222) is one of several vaccines introduced to provide immunity against SARS‐CoV‐2. Recently, more than 50 cases have been reported presenting a combination of thrombosis, thrombocytopenia, and remarkably high levels of anti‐platelet factor 4 (PF4)/polyanion antibodies post‐AZD1222 vaccination. Now linked to the vaccine, the condition is referred to as vaccine‐induced immune thrombotic thrombocytopenia. The European Medicines Agency still recommends vaccination with AZD1222, but several European countries have temporally paused and/or restricted its use because of the perceived risk of this severe side effect. Because there is no description of PF4/polyanion antibody testing in the clinical trials, knowledge about the prevalence of such antibodies in a vaccinated cohort is needed. Objectives To investigate prevalence of thrombocytopenia and anti‐PF4/polyanion antibodies in a population recently vaccinated with AZD1222. Patients/Methods Four hundred and ninety‐two health care workers recently vaccinated with the first dose of AZD1222 were recruited from two hospitals in Norway. Study individuals were screened for thrombocytopenia and the presence of anti‐PF4/polyanion antibodies with a PF4/PVS immunoassay. Side effects after vaccination were registered. Results The majority of study participants had normal platelet counts and negative immunoassay. Anti‐PF4/polyanion antibodies without platelet activating properties were only detected in six individuals (optical density ≥0.4, range 0.58–1.16), all with normal platelet counts. No subjects had severe thrombocytopenia. Conclusions We found low prevalence of both thrombocytopenia and antibodies to PF4/polyanion‐complexes among Norwegian health care workers after vaccination with AZD1222.

Immune aggregates organized as tertiary lymphoid structures (TLS) are observed within the kidneys of patients with systemic lupus erythematosus and lupus nephritis (LN). Renal TLS was characterized in lupus-prone New Zealand black  New Zealand white F1 mice analyzing cell composition and vessel formation. RNA sequencing was performed on transcriptomes isolated from lymph nodes, macrodissected TLS from kidneys, and total kidneys of mice at different disease stages by using a personal genome machine and RNA sequencing. Formation of TLS was found in antiedouble-stranded DNA antibodyepositive mice, and the structures were organized as interconnected large networks with distinct T/B cell zones with adjacent dendritic cells, macrophages, plasma cells, high endothelial venules, supporting follicular dendritic cells network, and functional germinal centers. Comparison of gene profiles of whole kidney, renal TLS, and lymph nodes revealed a similar gene signature of TLS and lymph nodes. The up-regulated genes within the kidneys of lupus-prone mice during LN development reflected TLS formation, whereas the down-regulated genes were involved in metabolic processes of the kidney cells. A comparison with human LN gene expression revealed similar up-regulated genes as observed during the development of murine LN and TLS. In conclusion, kidney TLS have a similar cell composition, structure, and gene signature as lymph nodes and therefore may function as a kidney-specific type of lymph node.

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Renal DNase I is lost in advanced stages of lupus nephritis. Here, we determined if loss of renal DNase I reflects a concurrent loss of urinary DNase I, and whether absence of urinary DNase I predicts disease progression. Mouse and human DNase I protein and DNase I endonuclease activity levels were determined by western blot, gel, and radial activity assays at different stages of the murine and human forms of the disease. Cellular localization of DNase I was analyzed by immunohistochemistry, immunofluorescence, confocal microscopy, and immunoelectron microscopy. We further compared DNase I levels in human native and transplanted kidneys to determine if the disease depended on autologous renal genes, or whether the nephritic process proceeded also in transplanted kidneys. The data indicate that reduced renal DNase I expression level relates to serious progression of lupus nephritis in murine, human native, and transplanted kidneys. Notably, silencing of renal DNase I correlated with loss of DNase I endonuclease activity in the urine samples. Thus, urinary DNase I levels may therefore be used as a marker of lupus nephritis disease progression and reduce the need for renal biopsies.

Divergent incommensurable models have been developed to explain the pathogenesis of lupus nephritis. Most contemporary models favor a central role for anti-chromatin antibodies. How they exert their pathogenic effect has, however, endorsed conflicts that at least for now preclude insight into definitive pathogenic pathways. The following paradigms are contemporarily in conflict with each other: i) the impact of anti-double-stranded DNA (dsDNA) antibodies that cross-react with inherent renal antigens, ii) the impact of anti-dsDNA antibodies targeting exposed chromatin in glomeruli, and iii) the impact of relative antibody avidity for dsDNA, chromatin fragments, or cross-reacting antigens. Aside from these three themes, the pathogenic role of T cells in lupus nephritis is not clear. These different models should be tested through a collaboration between scientists belonging to the different paradigms. If it turns out that there are different pathogenic pathways in lupus nephritis, the emerging pathogenic mechanism(s) may be encountered with new individual causal therapy modalities. Today, therapy is still unspecific and far from interfering with the cause(s) of the disorder. This review attempts to describe what we know about processes that may cause lupus nephritis and how such basic processes may be affected if we can specifically interrupt them. Secondary inflammatory mechanisms, cytokine signatures, activation of complement, and other contributors to inflammation will not be discussed herein; rather, the events that trigger these factors will be discussed.