Traditionally, 4 mechanisms of adaptive immune-triggered inflammatory responses were recognized:
Coombs and Gell elaborated on these mechanisms in 1962. A fifth category, stimulatory hypersensitivity, was described later. This system predated the discovery of T lymphocytes, at a time when understanding was limited to antibody-triggered mechanisms. Familiarity with Coombs and Gell type reactions is important for interpretation of older literature. However, it is more accurate to divide the effector responses of adaptive immunity into 3 main categories (Table 2-1):
Antibody-Mediated Immune Effector Responses
Structural and functional properties of antibody molecules
Structural features of immunoglobulins Five major classes of immunoglobulin (M, G, A, E, and D) exist, with 9 subclasses or isotypes (IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgE, and IgD). The basic immunoglobulin structure is composed of 4 covalently bonded glycoprotein chains that form a monomer of approximately 150,000–180,000 Da (Fig 2–6). Each antibody monomer contains 2 identical light chains, either kappa (κ) or lambda (λ), and 2 identical heavy chains from 1 of the 9 distinct subclasses of immunoglobulins; the type of heavy chain defines the specific isotype. IgM can form pentamers or hexamers in vivo, and IgA can form dimers in secretions, so the in vivo molecular size of these 2 classes is much larger than that of the others.
Antibodies contain regions called domains that carry out the specific functions of the antibody molecule. The Fab region (2 of which are present on each molecule) contains the antigen-binding domain, called the hypervariable region. The opposite end of the molecule, on the heavy chain portion, contains the attachment site for effector cells (the Fc portion, for fragment crystallizable). It also contains the site of other effector functions, such as complement fixation (for IgG3) or binding to a secretory component for transportation through epithelia and secretion into tears (for IgA). Table 2-2 summarizes the important structural differences among immunoglobulin isotypes.
Functional properties of immunoglobulins Immunoglobulin isotypes differ in how they mediate effector functions of antibody activity. Human IgM and IgG3 are good complement activators, whereas IgG4 is not. Only IgA1 and IgA2 can bind the secretory component and be actively passed into mucosal secretions. The importance of these differences is that 2 antibodies with identical capacity to bind to an antigen—but of different isotype—will produce different effector and inflammatory outcomes.
Table 2-2 Structural and Functional Properties of Immunoglobulin Isotypes
Clonality Each B cell creates, via genetic recombination, a unique Fab fragment that recognizes a single antigenic configuration. Proliferation of an individual B cell via cell division produces daughter cells that contain the same antigenic configuration. Continual clonal expansion results in a population of identical cells that recognize the same epitope, termed a monoclonal population. However, a foreign substance has many antigenic epitopes. Thus, many individual B cells will recognize various epitopes on the same substance, and each B cell will undergo simultaneous clonal expansion. The sum reactivity of all these antibodies is a polyclonal response that characterizes the typical immune response. Modern molecular biologic techniques allow the amplification of a single B-cell clone and production of large amounts of monoclonal antibodies for therapeutic purposes. Biologic drugs such as infliximab, adalimumab, and rituximab are examples of recombinant monoclonal antibodies.
Idiotypes Because they are proteins, antibodies themselves can be antigenic. Their antigenic sites are called idiotopes, as distinguished from epitopes, the antigenic sites on foreign molecules. Antibodies to idiotopes are called idiotypes. Anti-idiotypic antibodies may function as feedback mechanisms for immune regulation and have clinical significance for modern biologic therapies. Infliximab, for example, is a monoclonal chimeric (mouse and human) antibody to TNF-α that is used to treat some forms of uveitis. Efficacy of this drug may be limited by the development of anti-idiotype antibodies that neutralize the antigen binding site for TNF-α.
Infiltration of B lymphocytes into tissues and local production of antibody
B-lymphocyte infiltration B lymphocytes can infiltrate the site of an immunologic reaction in response to persistent antigenic stimulus. If the process becomes chronic, plasma cell formation occurs, with local production of antibody specific for the inciting antigen(s). If the antigen is known or suspected, as in the case of a presumed infection, assessment of local antibody production can serve as a diagnostic test.
Differentiation between local production of antibody and passive leakage from the blood to the intraocular compartment involves determination of the Goldmann-Witmer (GW) coefficient. This is calculated by comparing the ratio of specific IgG antibody present in intraocular fluid to the total IgG level in intraocular fluid versus the ratio of specific IgG level in serum to the total IgG level in serum:
The GW coefficient is used clinically in Europe, where an index of more than 3 indicates intraocular infection by the specific pathogen against which the antibody was produced. The GW coefficient was used to demonstrate that aqueous from eyes with Fuchs uveitis syndrome (FUS) had markedly elevated intraocular IgG titers to rubella virus compared with levels found in controls. The average GW coefficient was 20.6 in FUS patients, compared with less than 1.4 in controls.
Local antibody production within a tissue and chronic inflammation Persistence of antigen within a site, coupled with infiltration of specific B lymphocytes and local antibody formation, can produce a chronic inflammatory reaction called the chronic Arthus reaction. The histologic pattern often demonstrates lymphocytic infiltration, plasma cell infiltration, and granulomatous features. This mechanism may contribute to the pathophysiology of certain chronic autoimmune disorders, such as rheumatoid arthritis, which feature formation of pathogenic antibodies.
Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 9th ed. Philadelphia, PA: Elsevier/Saunders; 2018.
Foster CS, Streilein JW, Coma MC. Immune-mediated tissue injury. In: Albert DM, Jakobiec FA, Azar DT, Gragoudas ES, eds. Principles and Practice of Ophthalmology. 3rd ed. Philadelphia, PA: WB Saunders; 2008:chap 9.
Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.