While Fc subclass and its glycan composition are natural determinants of selective FcR engagement, further refinement has been achieved by engineering the Fc to optimize specific FcR interactions. in the study of antibodies, going back to 2′,5-Difluoro-2′-deoxycytidine Ehrlich at the turn of the twentieth century, appreciation of isotype diversity was not recognized. Rabbit polyclonal to IL22 Without doubt, one of the most pivotal studies was the paper by Howard Grey and Henry Kunkel published inJEMin April 1964, demonstrating that the 7S class of immunoglobulins (known as IgG today) consists of at least three distinct subclasses (Grey and Kunkel, 1964). Together with studies fromLichter and Dray (1964)andBallieux et al. (1964)in the same year, their paper highlighted that an 2′,5-Difluoro-2′-deoxycytidine unexpected additional layer of complexity exists beneath the well-known 7S, 19S (IgM), and b2A (IgA) antibody classes. Insights from Falk Nimmerjahn and Jeffrey V. Ravetch. IgG antibodies represent the most abundant immunoglobulin isotype in the serum, and a reduction or absence of IgG antibodies predisposes individuals to recurring infections, demonstrating the pivotal role of IgG in host defense. Conversely, self-reactive IgG antibodies (autoantibodies) play a major role in triggering tissue inflammation characteristic of autoimmune diseases such as systemic lupus erythematosus or inflammatory arthritis. In the treatment of autoimmune diseases and cancer, intact IgG antibodies or IgG-fragment crystallizable (Fc) fusion proteins have become the most widely used platform technology to target autoreactive or cancerous cells either directly or indirectly via modulation of immune responses. Adding to this multitude of IgG activities, polyclonal IgG preparations pooled from the serum of thousands of donors (also known as intravenous immunoglobulins, or IVIg) are able to suppress a wide variety of autoimmune and chronic inflammatory diseases, demonstrating that IgG antibodies can have both pro- and anti-inflammatory activities (Bournazos et al., 2017). The work of Grey and Kunkel provided the conceptual framework for these later studies by demonstrating that heterogeneity within IgG isotypes exists. In their paper,Grey and Kunkel (1964)made use of the fact that patients with multiple myeloma are characterized by an expansion of a single malignant B cell clone secreting large amounts of one intact IgG molecule or a single antibody light chain (also known as Bence Jones protein), respectively. By injecting purified 7S myeloma proteins obtained from different patients into rabbits, they were able to raise rabbit antisera directed against different human 7S myeloma proteins. Using these antisera against a set of 7S myeloma protein preparations in ouchterlony agar diffusion/precipitation assays, they demonstrated that at least three subgroups of 7S proteins exist and that their heterogeneity is located within the antibody heavy chain or Fc region (panel A in the figure). Their work further demonstrated that these IgG subclasses exist in normal human serum, emphasizing the general importance of their finding beyond multiple myeloma. Moreover, the generation of detection methods (antisera) for distinct IgG subclasses represented a major advance for the field, allowing for the assessment of how select IgG subclasses are generated during different types of immune responses. The complexity of IgG subclass activity. (A) Shown is an in-gel antibody precipitation assay (ouchterlony assay) fromGrey and Kunkel (1964), demonstrating that a rabbit antiserum generated against 2′,5-Difluoro-2′-deoxycytidine one myeloma IgG molecule precipitates some but not all IgG antibodies 2′,5-Difluoro-2′-deoxycytidine derived from other multiple myeloma patients (IgG from patient We is not precipitated, whereas 2′,5-Difluoro-2′-deoxycytidine IgG from patients Ap, Fe, Hu, and FrII is precipitated). The antiserum also reacted against normal human serum demonstrating the presence of IgG subclasses in healthy individuals. (B) Depicted are lung melanoma metastases in C57BL/6- and FcRIIb-deficient mice left untreated or treated with IgG subclass switch variants (IgG1 and IgG2a) of the melanoma-specific antibody TA99. (C) Shown are lung melanoma metastases in C57L/6 mice left untreated or treated with a TA99-IgG2b subclass variant carrying a sugar moiety with or without fucose in its Fc domain. (D) Schematic representation of factors influencing IgG activity. Apart from individual IgG subclasses, IgG glycosylation plays a major role in balancing the pro- and anti-inflammatory activities of IgG via modulating the interaction with type I and type II Fc-receptors (FcR). See text for further details. The results of Grey and Kunkel paved the way for identifying similar IgG subclasses in other species, such as mice and nonhuman primates, and allowed for the isolation and biochemical characterization of the four human IgG subclasses as we know them today (named IgG1, IgG2, IgG3, and IgG4;Rowe, 1970). The pivotal studies of Cooper in the 1970s demonstrating that antibodies switched from one isotype to another added a layer of complexity to the simplistic view that.