Structural characterization of the second major cross‐reactive idiotype group of human rheumatoid factors. Association with the V<sub>H</sub>4 Gene Family

We report the DNA sequences of the heavy and light chain immunoglobulin genes of 11 monoclonal rheumatoid factor (RF)-secreting lines derived from the peripheral blood of two patients with rheumatoid arthritis (RA). It is evident from immunogenetic analysis of these lines that RA-associated RF activity can arise from a wide variety of heavy and light chain genes and gene combinations. Although the RF response from our two patients shows a bias in gene usage toward those genes used to encode monoclonal RF, particularly VkIII, relatively few of these RFs are reactive with the monoclonal antiidiotypes 6B6.6 and 17.109 that define VkIII germline-encoded light chains and the loss of this idiotypic reactivity is clearly related to somatic mutation. Finally, RFs derived from peripheral blood of RA patients show a similar heterogeneity of epitope binding to Fc as that seen for synovium-derived RF and some are clearly different in binding specificity from the restricted RF population found in patients with B cell malignancies. Somatic mutations as well as different VH /VL combinations contribute to the heterogeneity in the binding patterns of these RA-derived RF. (J. Clin. Invest. 1994. 93:852-861.)

Section: Introductionmentioning

confidence: 99%

Rheumatoid factors from the peripheral blood of two patients with rheumatoid arthritis are genetically heterogeneous and somatically mutated.

Youngblood

Fruchter²,

Ding³

et al. 1994

“…In rheumatoid factors this particular light chain is typically associated with VHIII variable region genes. The Bla CRI is expressed on -15% of mixed cryoglobulin rheumatoid factors and detects an idiotope encoded by the same VKIIIa gene segment (HumKv328) as the Po CRI but Bla positive molecules are generally associated with heavy chains expressing VHIV variable region genes (20).…”

Section: Introductionmentioning

confidence: 99%

Rheumatoid factors isolated from patients with autoimmune disorders are derived from germline genes distinct from those encoding the Wa, Po, and Bla cross-reactive idiotypes.

Victor¹,

Randen²,

Thompson³

et al. 1991

104

To better understand the structural basis for rheumatoid factor activity, the nucleotide sequence of the light chain variable regions of nine human monospecific IgM rheumatoid factors were analyzed. Rheumatoid factors were isolated from three patients with rheumatoid arthritis, a patient with systemic lupus erythematosus, and a normal individual. The VL gene segments used by these rheumatoid factors are not as restricted as previous work on mixed cryoglobulin rheumatoid factors had suggested. Each of the different VK families is represented and there are two examples where a V, gene segment is used. Molecules with structures similar to those of the Wa and Po CRI, characteristic of mixed cryoglobulin rheumatoid factors, are not common among these rheumatoid factors isolated from patients with rheumatoid arthritis. While there are clear examples of rheumatoid factors that are direct copies of germline genes, most of the sequence data suggest that the processes of antigenic selection and somatic mutation contribute significantly to the generation of monospecific rheumatoid factors in patients with autoimmune disease. (J. Clin. Invest. 1991.

“…3. Except where indicated, these IgM use VJllI L chains, and usage was presented in earlier publications (6,8,13,14). For VH4, 0/1 VHS, and 3/4 VH6 IgM, displayed significant ELISA reactivity with pFv.…”

Section: Methodsmentioning

confidence: 97%

Superantigen properties of a human sialoprotein involved in gut-associated immunity.

Silverman

Roben²,

Bouvet³

et al. 1995

Protein Fv (pFv) is a recently described 175-kD gut-associated sialoprotein with a potent capacity for augmentation of antibody-dependent immune functions. To investigate the molecular basis for Fab-mediated binding of pFv, we evaluated a panel of 52 monoclonal IgM and found that -40% bound pFv. Whereas the majority (2 75% ) of VH3 and VH6IgM strongly bound pFv, only a small minority (< 20%) of IgM from other V H families bound pFv, and these antibodies had weaker binding interactions. Inhibition studies suggested that all binding occurred at the same (or overlapping) site(s) on pFv. Surface plasmon resonance studies demonstrated binding affinity constants up to 6.7 x 10 M-l for pFv. Biopanning of IgM and IgG Fab phage-display libraries with pFv preferentially selected for V H3 and V H6 antibodies, but also obtained certain V H4 1gM. V H sequence analyses of 36 pFv-binding antibodies revealed that binding did not correlate with CDR sequence, JH, or L chain usage. However, there was preferential selection of pFv binders with V H CDR3 of small size. These studies demonstrate that a protein which enhances immune defense in the gut has structural and functional properties similar to known superantigens. (J. Clin. Invest. 1995. 96:417-426.)