Activation and augmentation of complement cascades are well-known functions of certain classes of immunoglobulins. On the other hand, pooled immunoglobulins in supraphysiologic concentrations have the ability to inhibit harmful biological effects of activated complement fragments by diverting them away from their targets to the fluid phase, where they may be subject to further inactivation. Scavenging appears to be mediated by immunoglobulin fragment-specific acceptor sites. Domains within constant region of F(ab)’2 seem responsible for anaphylatoxin binding and neutralization, while Fc fragments interact with C3b and C4b. The ability to attenuate complement fragment- induced immune damage cannot be correlated with any known phenotypic marker used today to categorize immunoglobulins and could serve as a basis for a new classification of immunoglobulinsstrong versus weak inhibitors of complement fragment effects. The concept of dual effect of immunoglobulins on the complement system has implications for both novel physiologic functions of normal circulating immunoglobulins as well as clinical applications of high-dose intravenous immunoglobulin (IVIG).

Key words

immunoglobulins complement,

cascades anaphy, latoxins C3b/C4b, activation scavenging , IVIG 

1. INTRODUCTION

It has been a classic immunologic paradigm that specific immunoglobulins, following their binding to target antigens, trigger complement activation with subsequent cellular damage and initiation of the inflammatory reaction. In case of invasion by foreign microorganisms, such series of events is beneficial to the host, since it leads to the elimination of pathogens. However, the same sequence of events can be self-damaging if it is triggered under inappropriate circumstances, such as autoimmune reaction and/or over stimulation of the innate immunity by a pathogen. As it will be discussed in this chapter, immunoglobulins derived from the normal serum and modified for intravenous use in high doses (IVIG), have the ability to suppress and attenuate effects of activated complement fragments, including their pro-inflammatory capacity. Therefore, it appears that immunoglobulin molecules have ambivalent functions when it comes to their effects on the complement system and that the outcome (activation vs. inhibition) is determined by the immunoglobulin specificity.

2. COMPLEMENT ACTIVATION BY IMMUNOGLOBULINS

Classical complement pathway is initiated when a conformational change in IgG and IgM molecules bound to their antigen activates the first complement component complex -Clq,r,s. This triggers a domino-like effect in which classical pathway complement components (present in serum as inactive pro-enzymes) get activated by the previous component in the system (1). Immunoglobulins of IgD, IgE and IgA isotypes do not have the capacity to activate complement through the classical pathway (2). Among IgG subtypes, IgG1 and IgG3 are strong, IgG2 moderate activator of complement and IgG4 has no complement-activating properties at all (2). In general, IgG is not an efficient complement activator since C1 fixation requires two IgG molecules lying side-by-side in close proximity (so called “doublet”). The formation of a doublet occurs by chance; therefore, hundreds and thousands of IgG molecules have to be available in the process. On the other hand, a single IgM molecule, complexed with antigen on the cell surface, is sufficient to bind and activate C1; it was shown that as few as two IgM antibodies were sufficient to sensitize an erythrocyte (3).

Lectin pathway of complement activation is triggered when mannose– binding lectin (MBL) recognizes high-density arrays of terminal mannose residues on invading pathogens. Subsequent to MBL binding, MBLassociated serine proteases (MASP-1 and MASP-2) activate the classical pathway components 4 and 2 (4). MBL is structurally and functionally similar to C1q molecule of the classical pathway (1). Lectin pathway hemolysis was shown to be enhanced in-vitro by IgG, IgM and IgA molecules.

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