Biology subjects

Jumaa, H.

Publications and source records attributed to Jumaa, H..

3 recordsLinked to original sources

bioRxiv2021

Accumulation of the GSK3 target protein β-catenin is lethal for B cell precursors and malignant B cells

Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed kinase involved in a myriad of biological processes. Although GSK3 mediated phosphorylation has been shown to induce the degradation of many pro-survival and pro-proliferation factors, cancer cells of different origin show reduced proliferation or survival after GSK3 inhibition. Our current understanding of the role GSK3 plays in normal mature B cells, B cell precursors and transformed B cells is incomplete and does not allow to assess whether GSK3 inhibitors can be used to treat B cell derived malignancies. Here we identify {beta}-catenin as the major factor driving GSK3-inhibition induced changes in B cells. We show that {beta}-catenin accumulation has opposing effects on cell metabolism and survival in mature B cells and B cell precursors. Moreover, we demonstrate that {beta}-catenin destabilizes the commitment to the B cell lineage. In summary, our study identifies {beta}-catenin induced signaling as a factor that can be exploited to limit the survival of malignant B cells.

immunology↗

bioRxiv2021

Antibodies control metabolism by regulating insulin homeostasis

Homeostasis of metabolism by hormone production is crucial to maintain physiological integrity and disbalance can cause severe metabolic disorders such as diabetes mellitus. Here, we show that antibodies recognizing insulin are key regulators of blood glucose and metabolism controlling insulin concentrations. In fact, antibody-deficient mice and immunodeficiency patients show sub-physiological blood glucose, which becomes normal after total IgG injection. We show that insulin-specific IgG antibodies found in the serum of wildtype mice or healthy individuals are responsible for this regulation. Interestingly, we identify two fractions of anti-insulin IgM which differ in their affinity to insulin. The low affinity IgM fraction (anti-insulin IgMlow) neutralizes insulin and leads to increased blood glucose while the high affinity IgM fraction (anti-insulin IgMhigh) protects insulin from neutralization by anti-insulin IgG thereby preventing blood glucose dysregulation. In contrast to anti-insulin IgMhigh, anti-insulin IgMlow binds to dsDNA suggesting that it is multi-specific. This multi-specificity mediates the formation of larger immune complexes containing insulin which results in increased uptake and degradation of insulin by macrophages in the presence of anti-insulin IgMlow as compared to anti-insulin IgMhigh. To demonstrate that high affinity anti-insulin IgM acts as protector of insulin and counteracts insulin neutralization by anti-insulin IgG, we expressed the variable regions of the same anti-insulin antibody as IgG or IgM. Strikingly, only the anti-insulin IgM regulated insulin function and prevented IgG-mediated neutralization of insulin and subsequent blood glucose dysregulation. Since anti-insulin IgMhigh is generated in the course of an immune response and affinity maturation, its protective role suggests that preventing autoimmune damage and maintaining physiological homeostasis requires adaptive tolerance mechanisms that generate protective IgM antibodies during memory responses.

immunology↗

bioRxiv2020

An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation

BackgroundAberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes including chronic inflammatory diseases. Thus, the chemokine receptor CXCR4 is a promising target for the therapy of inflammatory disorders, such as atopic dermatitis or allergic asthma. A natural fragment of serum albumin, named EPI-X4, has previous been identified as endogenous peptide antagonist and inverse agonist of CXCR4. The endogenous CXCR4 antagonist provides a promising basis for the development of improved analogues for the therapy of inflammatory diseases. ObjectiveTo increase the anti-CXCR4 activity of EPI-X4 and to evaluate the therapeutic potential of optimized analogs in mouse models of atopic dermatitis and asthma. MethodsMolecular docking analysis of the interaction of EPI-X4 with CXCR4 was performed to define critical interaction motifs and to rationally design analogs with increased activity. EPI-X4 derivatives were synthesized and CXCR4 binding and antagonizing activity determined in assays for antibody competition, inhibition of CXCR4-mediated HIV-1 infection, CXCL12-dependent Ca2+ mobilization, ERK and AKT phosphorylation and cell migration. Toxicity of peptides was evaluated in zebrafish embryos. The therapeutic efficacy of the lead peptide EPI-X4 JM#21 was determined in mouse models of atopic dermatitis and asthma. ResultsDocking analysis identified key interaction motifs of EPI-X4/CXCR4. Rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4 and resulted in the generation of the lead analog JM#21, which bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100. JM#21 did not exert toxic effects in zebrafish embryos and efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis. Moreover, EPI-X4 and its improved derivative suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model. ConclusionThe rationally designed EPI-X4 derivative JM#21 is a potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis. Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis, asthma and other CXCR4-associated diseases is highly warranted. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

immunology↗