The effects of complement-coated antigens on antibody responses are mediated primarily through complement receptors CD21 (CR2) and CD35 (CR1). CD21 and CD35 are expressed predominantly on B lymphocytes and FDCs.  CD35 is also found on polymorphonuclear cells, macrophages, mast cells, and DCs. CD21 and CD35 are encoded for by separate yet closely linked genes in humans. In mice, CD21 and CD35 originate from the same locus ( Cr2) and are generated by alternative splicing events at the RNA level.

Two novel sets of experiments demonstrated that CD21 and CD35 are important in regulating B-lymphocyte responses to T-dependent antigens. In the first set of experiments, antibodies specific for both CD21 and CD35 or CD35 alone were administered to immunized mice. In the second set of experiments, a soluble form of CD21 was administered to immunized mice, thereby competing for C3d-coupled antigen interactions. In both sets of experiments, treatment impaired antibody responses. In the first approach, the antibody that specifically blocked the interaction of C3d with CD21 was much more effective at blocking antibody responses compared with anti-CD35 antibody treatment, which blocked only the binding of C3b to CD35. This suggested that although both receptors con tribute, CD21 is more important in regulating antibody responses.

Because CD21 and CD35 are found on B lymphocytes and FDCs, two important cell types for humoral responses, two non-mutually exclusive models are proposed for their function. In the first model, CD21 augments antibody responses through activity as a coreceptor on B lymphocytes ( Fig. 1A ). The second model proposes that CD21/CD35 on FDCs trap and focus antigen such that B lymphocytes can efficiently cross-link their antigen receptor to become activated (see Fig. 1B ).

Fig1. COUPLING OF C3D TO ANTIGEN ALTERS ITS FATE IN B-CELL RESPONSE. (A) Coligation of the B-cell receptor (BCR) with the CD19/ CD21/CD81 complex by antigen coated with C3d regulates essential functions for naïve B-cell activation. The boxed area indicates the key binding interaction between CD21/CR2(SCR1-2), and the C3d fragment that is covalently bound (yellow triangle) to the antigen recognized by this B cell’s BCR. (B) C3d-coated anti gens are also captured on the surface of the follicular dendritic cells (FDCs) by CD21, allowing for efficient stimulation of previously antigen-engaged B-cell centro cytes in the germinal centers during the process of affinity maturation and the generation of memory B cells. (C) The structure of the CR2(SCR1–2):C3d complex as a surface representation of C3d colored for electrostatic potential ( red, negative; blue, positive) and an overlayed, semitransparent, ribbon diagram of CR2(SCR1–2) showing stick models of the side chains of some of the interacting residues. Note the charge complementarity for many of the interacting amino acids. (C, Reproduced with permission from van den Elsen JM, Isenman DE. A crystal structure of the complex between human complement receptor 2 and its ligand C3d. Science. 2011;332:608.)

As is apparent from the schematics in Fig. 1A and B , and as will be elaborated upon further in the ensuing discussion, the key ligand receptor–receptor interaction mediating the linkage between complement and the adaptive humoral immune system is that between the C3d fragment that is covalently coupled to antigen and CD21 (CR2) present on B cells and FDC. The extracellular region of CD21 is com posed of 15 or 16 SCR domains (because of the usage of alternative splice sites for exon 11), but the C3d binding site is confined to the two N-terminal–most SCR domains. 147 In what is an instructive lesson on the need to have concordance between x-ray crystallographic structures and biochemical data, the nature of this important interface had been hotly debated for a decade because of discrepancies between a structure of the CR2 (SCR1-2):C3d complex published in 2001 with both preexisting and subsequent biochemical data in the literature. A 2011 de novo structure of this complex, depicted in Fig. 1C , appears to have resolved the issue because the interactions seen in the new structure are fully supported by the biochemical data in the literature. For example, the biochemical data suggesting that there should be multiple ionic bonds mediating the binding is fully rationalized in terms of the five such bonds seen in the structure between a very negatively charged interface on a concave face of C3d that is remote from the covalent attachment site and positively charged lysine and arginine side chains from CR2 sticking down and interacting with oppositely charged residues on the C3d interface, as can be appreciated in Fig. 1C .

As a coreceptor, engagement of CD21 by complement-coupled antigen on the surface of a B lymphocyte, in combination with mem brane Ig (BCR) cross-linking, would lower the threshold of signal through the BCR required to activate the cell. Accordingly, naïve B lymphocytes bear low-affinity receptors for antigen; therefore, especially under conditions of limiting antigen, as would be the case during initial encounter with a microbial pathogen, additional signaling by the CD21 coreceptor is required for efficient activation. This was demonstrated in vitro by culturing B lymphocytes with cognate anti gen, either uncoupled or coupled to C3d. By measuring intracellular Ca 2+ levels as a measure of cell activation, it was estimated that 100- to 1000-fold less C3d-conjugated antigen was required to activate B lymphocytes compared with unconjugated antigen.

The opportunity to test the importance of CD21 and CD35 as B-lymphocyte coreceptors in vivo came from studies using mice with targeted disruption in the Cr2 locus. Importantly, Cr2-deficient mice have impaired humoral responses similar to C1q-, C4-, and C3-deficient mice (Fig.2). Using embryonic stem cells with a disrupted Cr2 locus, Croix et al. used blastocyst complementation of Rag2 −/− mice, such that chimeric mice expressed CD21/CD35 on FDCs but not on B lymphocytes. These chimeric mice displayed impaired antibody responses to the T-dependent antigen NP-KLH compared with control subjects. Therefore CD21/ CD35 on B lymphocytes is important for normal antibody responses. Although CD21/CD35 on FDC is on its own insufficient for normal antibody responses, as discussed in the next section, CD21/CD35 on FDC does have a specific role in the memory response of B-cell mediated immunity.

The covalent attachment of complement to antigen engages CD21 as a complex with CD19/CD81 and BCR on the cell surface (see Fig. 1A ). Dual binding of CD21/CD19/CD81 with BCR generates a stronger signal compared with BCR engagement alone. If the combined signal is sufficient, the B lymphocyte is activated. If insufficient, then the B lymphocyte is likely eliminated by apoptosis. The major ligand-binding receptor within the CD21/CD19/CD81 complex is CD21. The major role of CD19 is in initiating a signaling cascade within the cell. CD81 is a tetra spanning molecule that stabilizes the complex within the membrane. After coligation of the BCR with the CD21/CD19/CD81 complex, CD81 gets S-palmitoylated on a cysteine side chain, and this in turn mobilizes the coligated complexes to a special compartment of the plasma membrane known as a lipid raft. Localization to this compartment facilitates prolonged intracellular signaling because the compartment is rich in signal-propagating phosphokinases but is relatively devoid of the regulatory phosphatases. Absence of any of the CD21/CD19/CD81 components adversely affects antibody responses to T-dependent antigens, although the degree of impairment varies.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم التطوير يقيم دورة عن أخلاقيات المهنة للمنتسبين الجدد

تتضمن زيارة المراقد المقدسة في كربلاء.. معهد القرآن الكريم النسوي ينظم سفرة دينية لطالباته

المجمع العلمي يحتفي بذكرى ولادة الإمامين الباقر والهادي (عليهما السلام)

قسم الشؤون الفكرية يطلق فعاليات الأسبوع الثالث من برنامج البذرة الصالحة

المزيد

الآخبار الصحية

ثورة طبية.. الذكاء الاصطناعي يكشف سرطان الكلى في وقت قياسي

لتعزيز الطاقة والتغلب على التعب.. عليك بـ7 طرق بسيطة

لتحسين الهضم والتحكم في الشهية.. ما أفضل وقت لتناول التمر؟

خبراء يكشفون تأثير الاستحمام في الظلام على جودة النوم !

المزيد

الآخبار التكنلوجية

إزالة ثاني أكسيد الكربون من الغلاف الجوي.. ما دور المحيطات والبحار؟

نظائر الهيليوم مقياس لاكتشاف رواسب الذهب.. كيف ذلك؟

الصين تطلق أول ناقلة نفط خام ذكية في العالم تعمل بالميثانول

الزمن على المريخ أسرع من الأرض.. دراسة علمية تكشف الفوارق

المزيد

مواضيع ذات صلة

The Complement System : Alternative Pathway

The Complement System : Lectin Pathway

The Complement System: Classical Pathway

Secondary Lymphoid Tissue

The Hematopoietic Microenvironment

The Pro-B- and Pre-B-Cell Checkpoints

Immunoglobulin Gene Rearrangement : Heavy Chain Gene Rearrangement

Transcriptional Regulation of B-Cell Development

Stages of B-Cell development

Genetic Engineering of Natural Killer Cells

The role of Natural Killer Cells in Human Disease

Natural Killer Cells and Hematopoietic Cell Transplantation