Epistatic effects of Siglec-G and DNase1 or DNase1l3 deficiencies in the development of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a severe autoimmune disease that displays considerable heterogeneity not only in its symptoms, but also in its environmental and genetic causes. Studies in SLE patients have revealed that many genetic variants contribute to disease development. However, often its etiology remains unknown. Existing efforts to determine this etiology have focused on SLE in mouse models revealing not only that mutations in specific genes lead to SLE development, but also that epistatic effects of several gene mutations significantly amplify disease manifestation. Genome-wide association studies for SLE have identified loci involved in the two biological processes of immune complex clearance and lymphocyte signaling. Deficiency in an inhibitory receptor expressed on B lymphocytes, Siglec-G, has been shown to trigger SLE development in aging mice, as have mutations in DNA degrading DNase1 and DNase1l3, that are involved in clearance of DNA-containing immune complexes. Here, we analyze the development of SLE-like symptoms in mice deficient in either Siglecg and DNase1 or Siglecg and DNase1l3 to evaluate potential epistatic effects of these genes. We found that germinal center B cells and follicular helper T cells were increased in aging Siglecg -/- x Dnase1 -/- mice. In contrast, anti-dsDNA antibodies and anti-nuclear antibodies were strongly increased in aging Siglecg-/- x Dnase1l3-/- mice, when compared to single-deficient mice. Histological analysis of the kidneys revealed glomerulonephritis in both Siglecg -/- x Dnase1 -/- and Siglecg-/- x Dnase1l3-/- mice, but with a stronger glomerular damage in the latter. Collectively, these findings underscore the impact of the epistatic effects of Siglecg with DNase1 and Dnase1l3 on disease manifestation and highlight the potential combinatory effects of other gene mutations in SLE.

CD22 Controls Germinal Center B Cell Receptor Signaling, Which Influences Plasma Cell and Memory B Cell Output.

Germinal center reactions are established during a thymus-dependent immune response. Germinal center (GC) B cells are rapidly proliferating and undergo somatic hypermutation in Ab genes. This results in the production of high-affinity Abs and establishment of long-lived memory cells. GC B cells show lower BCR-induced signaling when compared with naive B cells, but the functional relevance is not clear. CD22 is a member of the Siglec family and functions as an inhibitory coreceptor on B cells. Interestingly, GC B cells downregulate sialic acid forms that serve as high-affinity ligands for CD22, indicating a role for CD22 ligand binding during GC responses. We studied the role of CD22 in the GC with mixed bone marrow chimeric mice and found a disadvantage of CD22-/- GC B cells during the GC reaction. Mechanistic investigations ruled out defects in dark zone/light zone distribution and affinity maturation. Rather, an increased rate of apoptosis in CD22-/- GC B cells was responsible for the disadvantage, also leading to a lower GC output in plasma cells and memory B cells. CD22-/- GC B cells showed a clearly increased calcium response upon BCR stimulation, which was almost absent in wild-type GC B cells. We conclude that the differential expression of the low-affinity cis CD22 ligands in the GC normally results in a strong attenuation of BCR signaling in GC B cells, probably due to higher CD22-BCR interactions. Therefore, attenuation of BCR signaling by CD22 is involved in GC output and B cell fate.

Medication and participation: A qualitative study of patient experiences with antipsychotic drugs.

Patient autonomy is recognised within mental healthcare, although the capacity to participate in one's own treatment planning is often reduced during a psychotic crisis. The patient may not be sufficiently competent to give consent or express preferences at the time treatment decisions are made. Nine participants were interviewed shortly after a crisis. We discussed participation in the treatment planning and recovery process with particular emphasis on interactions with professionals and understanding treatment. The participants recognised the need for drugs and mental healthcare but emphasised the need for better cooperation and communication. To facilitate the development of patient autonomy, we recommend an increased emphasis on providing information and participating in a dialogue about drug treatment options. This could counteract many of the negative experiences reported. The use of debriefing during hospitalisation and following coercion can be a practical tool for clarifying patient preferences and mutual understanding.