scholarly journals Insights Into the Structure-Function Relationships of Dimeric C3d Fragments

2021 ◽  
Vol 12 ◽  
Author(s):  
Ayla A. Wahid ◽  
Rhys W. Dunphy ◽  
Alex Macpherson ◽  
Beth G. Gibson ◽  
Liudmila Kulik ◽  
...  
Keyword(s):  
Cell Activation ◽  
Fluid Phase ◽  
Complement Receptor ◽  
Novel Therapies ◽  
B Cell Activation ◽  
Binding Studies ◽  
Surface Deposition ◽  
X Ray ◽  
Complement Receptor 2 ◽  
Spontaneous Formation

Cleavage of C3 to C3a and C3b plays a central role in the generation of complement-mediated defences. Although the thioester-mediated surface deposition of C3b has been well-studied, fluid phase dimers of C3 fragments remain largely unexplored. Here we show C3 cleavage results in the spontaneous formation of C3b dimers and present the first X-ray crystal structure of a disulphide-linked human C3d dimer. Binding studies reveal these dimers are capable of crosslinking complement receptor 2 and preliminary cell-based analyses suggest they could modulate B cell activation to influence tolerogenic pathways. Altogether, insights into the physiologically-relevant functions of C3d(g) dimers gained from our findings will pave the way to enhancing our understanding surrounding the importance of complement in the fluid phase and could inform the design of novel therapies for immune system disorders in the future.

scholarly journals Insights into the role of C3d dimers in B cell activation and Staphylococcal immune evasion

2020 ◽  
Author(s):  
A.A. Wahid ◽  
R.W. Dunphy ◽  
A. Macpherson ◽  
B.G. Gibson ◽  
L. Kulik ◽  
...  
Keyword(s):  
B Cell ◽  
Immune Evasion ◽  
Cell Activation ◽  
Fluid Phase ◽  
B Cell Activation ◽  
Binding Studies ◽  
Surface Deposition ◽  
Flow Cytometric ◽  
Cellular Tolerance

AbstractCleavage of C3 to C3a and C3b plays a central role in the generation of complement-mediated defences. Although the thioester-mediated surface deposition of C3b has been well-studied, fluid-phase dimers of C3 fragments remain largely unexplored. Here we present the first X-ray crystal structures of disulphide-linked human C3d dimers and show they undergo structurally-stabilising N-terminal domain swapping when in complex with the Staphylococcus aureus immunomodulator Sbi. Through binding studies and flow cytometric analyses we uncover the physiologically-relevant roles of these dimers in crosslinking complement receptor 2 and modulating B cell activation to potentially promote anergy. This potential induction of cellular tolerance by C3d dimers could contribute to Sbi-mediated S. aureus immune evasion as well as limit autoreactive immune responses under physiological conditions. Thus, insights gained from our findings could inform the design of novel therapies for autoimmune disorders and enhance our understanding surrounding the importance of complement in the fluid phase.

scholarly journals Complement Receptor Type 1 Suppresses Human B Cell Functions in SLE Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Mariann Kremlitzka ◽  
Bernadett Mácsik-Valent ◽  
Anna Polgár ◽  
Emese Kiss ◽  
Gyula Poór ◽  
...  
Keyword(s):  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Receptor Type ◽  
Complement Receptor ◽  
B Cell Activation ◽  
Complement Receptor Type ◽  
Cell Functions ◽  
Inhibitory Capacity

Complement receptors (CRs) play an integral role in innate immunity and also function to initiate and shape the adaptive immune response. Our earlier results showed that complement receptor type 1 (CR1, CD35) is a potent inhibitor of the B cell receptor- (BCR-) induced functions of human B lymphocytes. Here we show that this inhibition occurs already at the initial steps of B cell activation since ligation of CR1 reduces the BCR-induced phosphorylation of key signaling molecules such as Syk and mitogen activated protein kinases (MAPKs). Furthermore, our data give evidence that although B lymphocytes of active systemic lupus erythematosus (SLE) patients express lower level of CR1, the inhibitory capacity of this complement receptor is still maintained and its ligand-induced clustering results in significant inhibition of the main B cell functions, similar to that found in the case of healthy individuals. Since we have found that reduced CR1 expression of SLE patients does not affect the inhibitory capacity of the receptor, our results further support the therapeutical potential of CD35 targeting the decrease of B cell activation and autoantibody production in autoimmune patients.

B cell activation leads to shedding of complement receptor type II (CR2/CD21)

2003 ◽  
Vol 33 (9) ◽  
pp. 2391-2397 ◽  
Author(s):  
Madhan Masilamani ◽  
Daniela Kassahn ◽  
Stefan Mikkat ◽  
Michael O. Glocker ◽  
Harald Illges
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
Receptor Type ◽  
Complement Receptor ◽  
Type Ii ◽  
B Cell Activation ◽  
Complement Receptor Type

scholarly journals Human B cell activation. Evidence for diverse signals provided by various monoclonal anti-IgM antibodies.

1985 ◽  
Vol 162 (4) ◽  
pp. 1236-1255 ◽  
Author(s):  
S M Rudich ◽  
R Winchester ◽  
P K Mongini
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Activation ◽  
B Cell Activation ◽  
Binding Studies ◽  
Binding Characteristics ◽  
Low Concentrations ◽  
High Concentrations ◽  
The Individual ◽  
Cell Supernatant

Seven murine monoclonal antibodies (mAb) with different binding characteristics for human IgM varied markedly in their ability to induce proliferation of T cell-depleted human splenocytes. Two mAb (HB57 and 5D7) that bound to distinct epitopes on IgM were highly effective initiators of B cell proliferation at very low concentrations, in the presence of a T cell factor source. In the absence of T cell supernatant, both HB57 and 5D7 mAbs produced a markedly reduced degree of stimulation at all concentrations. Two additional anti-IgM mAb (VIIIE11 and Mu53) were distinctive in that, even at high concentrations, only limited proliferation was observed compared with the first group of mAb. This proliferation depended on the presence of T cell supernatant. Competitive-binding studies revealed that the epitope recognized by mAb Mu53 may be identical or very proximate to that recognized by HB57. Three other mAb (1G6, XG9, and P24) induced little or no proliferation. 1G6 bound to a unique epitope on the IgM molecule, whereas XG9 shared a determinant with VIIIE11 mAb. Regulatory influences of Fc receptor binding cannot account for all the diversity in proliferation observed with the individual anti-IgM mAb. Markedly augmented proliferation was obtained when B cells were cultured with certain combinations of anti-IgM mAb in the presence of exogenous T cell supernatant. The proliferation induced in the absence of T cell supernatant by high concentrations of mAb mixtures that included 1G6 approached that observed for the same mixtures in the presence of T cell supernatant. The data suggest that certain signals delivered through membrane IgM can bypass the need for T cell supernatant in the activation of human B lymphocytes.

scholarly journals Complement receptor 2 (CR2/CD21)

2017 ◽  
Vol 5 (4) ◽  
pp. 1156
Author(s):  
Rozaleen Dash ◽  
Nibhriti Das
Keyword(s):  
Cell Activation ◽  
B Lymphocyte ◽  
Lymphocyte Activation ◽  
Structural Similarity ◽  
Complement Receptor ◽  
Type I ◽  
B Cell Activation ◽  
Barr Virus ◽  
Inflammatory Conditions ◽  
Cell Immunity

Human complement receptor type 2 (CR2/CD21) is a surface-associated glycoprotein which binds to a variety of endogenous ligands, including the complement component C3 fragments iC3b, C3dg and C3d, the low-affinity IgE receptor CD23, and the type I cytokine, interferon-alpha. This receptor serves as an important interface between the complement system and adaptive immunity. It is expressed on B-lymphocytes, follicular dendritic cells, some epithelial cells, peripheral blood T cells. CR2 also play an important role in enhancing humoral immunity to T-dependent and T-independent foreign antigens and in regulating T-cell immunity to self and non-self-antigens. It is an important receptor that amplifies B lymphocyte activation by bridging the innate and adaptive immune systems. CR2 ligands include complement C3d and Epstein-Barr virus glycoprotein 350/220. Regions of EBV have structural similarity to C3dg, which allows it to bind CR2, and thereby gain access to cell’s interior. It also acts as receptor for other components or activators of innate immunity such as IFN-α, an anti-viral cytokine and DNA-DNA containing complexes such as chromatin. The binding of CR2 to IFN-α is speculated to cause B cell activation but their roles are still not clear. Variations or deletions of the CR2 gene in humans, or the Cr2 gene in mice associate with a variety of autoimmune and inflammatory conditions.

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