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Physicochemical and Functional Relationships of Immune Complexes 0022-202X/ 80/ 7405-0333$02.00/ 0 THE .J OURNAL OF I NVESTIGATIVE DERMATOLOGY, 74 :333-338, 1980 Vol. 74. No. 5 Copyright © 1980 by T he Williams & Wilkins Co. Printed in U. S.A. Physicochemical and Functional Relationships of Immune Complexes MART MANNIK, M.D. Division of Rheumatology, Department of Medicine, University of Washington, Seattle, Washington, U.S.A . The biological properties of immune complexes depend immune complexes. In any given immune complex the number on the nature of antigens and antibodies comprising of antigen and antibody molecules may vary, depending on the these complexes. The lattice of immune complexes influ­ characteristics of each of the reactants and the nature of the ences t h eir tissue deposition, complement activation, antigen-antibody union. The biological properties of immune and interaction with Fe receptors. The lattice of immune complexes are related to the properties of the molecules forming complexes d epends on the valence of antigens, the anti­ the complexes, as well as the number of reactants in each gen-antibody ratio, the association constant of these complex. reactants and the concentration of antig ~n and antibody. Antigens are defined as substances that interact specifically Kupffer cells effectively remove large-latticed immune with availa ble a ntibodies or sensitized l ymphocytes. The term complexes from the circulation due to their Fe receptors. immunogen, on the other hand, is reserved for a substance that This system is saturable, leading to prolonged circula­ upon administration to a s uitable host will elicit a n immune tion of the complexes a nd enhanced deposition in tissues. response. This distinction is made because all substances that Small-latticed immune complexes are slowly removed react with antibodies or with sensitized lymphocytes do not from the circulation by yet unidentified mechanisms. necessarily induce an immune response. The actual portion of The renal glomerulus serves as an example of immune an antigenic molecule that reacts with the a ntibody combining complex deposition from the circulation. Only large-lat­ site or with the s pecific receptor on a sensitized lymphocyte is ticed complexes are deposited in the glomerular capil­ defined as the antigenic determinant. The number of antigenic lary wall in the subendothelial area and the m esangial determinants on a molecule defines its valence for the interac­ matrix. An influx of bone marrow-derived monocytes tion wi th a specific antibody. An antigenic molecule may have participates in the disposal of immune complexes depos­ the valence of one for a given antibody specificity, but a number ited in these areas of the glomerulus, the resident mes­ of naturally occurring molecules have repeating chemical struc­ angial cells do not phagocytize these substances. The tuTes, thus g iving a n antigenic valence of more t han one. Fur­ subepithelial d eposits of immune complexes appear to th ~ rmor e, a given molecule may have different antigenic deter­ be locally formed and not deposited from the circulation. minants and thus able to react with antibodies of different specificities. Thus, a macromolecule may be mutivalent with respect to one or more specificities. The number of antigenic Immune complexes cause a variety of clinical disorders, af­ determinants of a molecule profoundly influences the kind of fecting various sizes of blood vessels, renal glomeruli, renal antigen-antibody complexes that may form with specific anti­ tubules, thyroid gland, c horoid plexus and other organs. The bodies. For detailed discussion of antigens and antigenic deter­ pathogenic immune complexes are either deposited from the minants t he interested r eader should consult immunochemical circulation or locally formed. In local formation of immune texts (1, 2]. complexes the antigens are part of the· organ or unrelated Antibodies, as the other essential constituents of immune antigens are selectively deposited in the organ and antibodies complexes, may belong to IgG, IgA, IgM, IgD or IgE class of from the circulation react with these antigens. In this patho­ immunoglobulins. IgG, monomeric IgA, IgD and IgE have a genic mechanism characteristically one organ system i s in­ valence of 2, i. e., each of these molecules has 2 binding sites volved and immune complexes are not present in the circula­ for a given antigen. Dimeric IgA has a valence of 4. lgM has a tion. On the other hand, when immune complexes are present valence of 5 or 10, depending on th e nature in the circulation, usually more than one organ is involved due of antigen molecules. For detailed discussion to deposition of these materials from circulation. In this a1·ticle of various a ntibody molecules, the reader should consult appropriate reviews [1,3,4]. the nature and biological properties of immune complexes will When the antigen-antibod be briefly reviewed. The relationship between the composition y union occurs, a variety of im­ mune complexes m ay form, ranging from of immune complexes and their fate in cil:culation will be an immune complex discussed with particular emphasis on the role of the mononu­ consisting of 1 antigen m olecule a nd 1 sntibody m olecule (Ag ~, Abt) to immune complexes clear phagocyte system in removal of circulating immune com­ consisting of many molecules of each r eacta plexes. Since detailed experimental data ar e not available on n t. The lattice of immune complexes thus reflects the relationship between the composition of immune complexes the number of antigen and number of antibody molecules in each complex. T he lattice and their deposition in skin, this relationship will be examined of an immune complex in turn for renal glomeruli. influences its biological properties. The lattice of immune complexes is influenced by several THE NATURE AND PROPERTIES OF IMMUNE variables. As all·eady pointed out, the valence of most antibodies COMPLEXES is 2. Detailed studies with polymeric IgA and IgM have not been conducted. The valence of antigen molecules significantly Antigens and antibodies aTe t he essential constituents of all influences the lattice of immune complexes that can be formed with given antibodies. A monovalent a ntigenic molecule can The work from our laboratories was in part supported by Resea1·ch only form Ag2Ab1 complexes and larger lattices or immune Grant AM 11476 and Research Training Grant T32AM7108, b oth from precipitates can not the National Institute of Arthritis, Metabolism and Digestive Diseases. be generated. Bivalent antigens, depending Reprint req uests to: Mart Man nik, M.D., Division of Rheumatology, on the distance between the antigenic determinants, may form Department of Medicine, Uni versity of Washington, Seattle, Washing­ Ag t Ab ~, Ag2Abz, cil'cular Ag3Ab3 or larger open or closed com­ to n 98195. plexes [5]. Such small-latticed immune complexes are soluble. Abbreviations: Only multivalent an tigens can form immune complexes with HSA: human serum albumin high degrees of lattice and undergo immune precipitation. MPS: mononuclear phagocyte system With multivalent antigens the molar r atio of antigens and 333 334 MANNIK Vol. 74, No.5 antibodies influence t he degree of lattice formation as best molecules attach to these receptors weakly, but do not lead to illustrated by the classic precipitin curves. At the point of interiorization of the molecules. Attachment of large-latticed equivalence maximum amount of antigen- antibody precipitate complexes (defined as containing more than 2 antibody mole­ is formed and free antigen and free antibody are not detectable cules) results in firmer attachment of the complexes and cul­ in the supernatant. Addition of excess antigen beyond the point minates in their phagocytosis. Evidence for these conclusions of equivalence leads to formation of soluble immune complexes has been obtained by examining complexes with oligovalent and a decrease in the a mount of immune precipitate. At rela­ and multivalenc antigens [14], immune complexes with known tively low degrees of antigen excess soluble large-latticed im­ degrees of lattice formation [15, 16], and with covalently cross­ mune complexes are formed, but with increasing a ddition of linked immune complexes with discrete degrees of lattice for­ excess antigen only small-latticed immune complexes are ob­ mation [17]. Complement is not essential for the attachment of tained. For example, with high degrees of excess human serum soluble immune complexes to the Fe receptor of monocytes albumin (subsequently abbreviated HSA) to a given amount of [15]. The phagocytosis and degradation of soluble immune antibodies to HSA only Ag,Ab, and Ag2Ab2 complexes were complexes, however, was facilitated by the presence of comple­ formed [6]. Fw·thermore, the absolute concentration of antigen ment [18]. and antibody will influence the degree of lattice formation. At The interaction of soluble immune complexes, containing IgG a given degree of antigen excess more small-latticed immune molecules, with the Fe receptors is of fu ndamental importance complexes are formed at microgram concentrations of the reac­ to the fate of immune complexes in circulation, as will be tants than at the same antigen-antibody ratio in milligram discussed in the next section. Furthermore, during the phago­ concentration of the reactants. cytosis of large-latticed immune complexes, particularly when The association constant between the a ntigen and antibody these substances are attached to nonphagocytizable surface, will influence lattice formation. When the association constant lysosomal enzymes spill in to the surroundings. This event is is low, small-latticed immune complexes tend to be formed, thought to be important in leading to tissue damage after whereas large-latticed immune complexes can form when the immune complex deposition or formation in tissues. The phag­ association constant is high and the antigen-antibody ratio is ocytosis of immune complexes also causes activation of macro­ appropriate [7]. phages with additional biologic properties as discussed earlier The immunochemical characteristics of immune complexes in this workshop.
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