and SAg recognition23
are germline V gene encoded functions. The expression of these functions is subject to deterioration or improvement due to biased germline gene usage; V-D-J/V-J sequence diversification; the VH/VL combination; and somatic hypermutation occurring at the FRs/CDRs. IgMs and IgAs preferentially express gp120 SAg hydrolyzing activity, with only low level activity evident in IgGs.11
The activity levels of polyclonal Igs from different humans of individual monoclonal Igs are highly variable. No obvious antigenic stimulus driving the synthesis of the catalytic Igs exists in humans who are not infected with HIV. Occam’s razor suggests consideration of a random distribution of the SAg-selective catalytic activity that is expressed fortuitously as the Igs mature adaptively in response to irrelevant antigenic stimuli. However, studies summarized below suggest that the gp120 SAg hydrolyzing (and neutralizing) activity is open to selection and improvement under certain circumstances.
Polyclonal IgGs from patients with lupus but no HIV infection and mouse lupus models24
bind the 421–433 gp120 region at levels superior to controls without autoimmune disease. We isolated Ig light chain subunits (IgLs) and HIV neutralizing single chain Fv fragments that recognize the 421–433 epitope from lupus Ig libraries.17, 25
Mutations are frequent in the FRs and CDRs of these clones. Some of the Ig fragments catalyze the cleavage of gp120.17
We and others reported the tendency towards enhanced catalytic Ig synthesis in autoimmune disease.26, 27
Several groups have noted that HIV infection is infrequent in lupus patients.28, 29
Increased 421–433 binding and hydrolyzing Igs may be the reason. A generalized increase of polyreactive Igs to microbial proteins is an unlikely explanation, as the lupus Ig binding, hydrolytic and neutralizing activities are specific for the 421–433 region.
Concerning the antigenic stimulus driving synthesis of the 421–433 recognizing Igs without HIV infection, we found no human proteins in the databanks with sequence similarity to the gp120 421–433 region. However, 27 of 39 nucleotides that code for the consensus clade B residues 421–433 (CCGTATGTAACGAAAAGGATGAAAGACGGTGTACAAATA) are identical to a human endogenous retroviral sequence (HERV; TTAGAT
; identities underlined; nucleotides 303–341, rv 012650, family HERVL47).17
Expression of human endogenous retroviral sequences (HERVs), which constitute up to 8% of the human genome, is increased in lupus.30
Interestingly, certain anti-gp120 Igs are reported to recognize a HERV expressed by placental tissue.31 S. gordonii
is a commensal bacterium that colonizes mucosal sites at varying densities. A probable transcription regulator-like (PRL) protein from this bacterium contains a peptide region homologous to gp120 residues 421–432 as shown below:
|S.gordonii PRL protein||77||KQFIINMSQNVGK||89|
Regrettably, amplification of protective catalytic Igs to the SAg is not routine in HIV infected subjects. However, we observed that prolonged infection for 5 years in a subpopulation of HIV infected individuals who remained AIDS-free is associated with a modest increase of catalytic IgAs to gp120.11
No increase was observed at an earlier stage in infection (6 months). In contrast, robustly increased conventional Igs with binding activity directed to the non-SAg gp120 epitopes were evident at this time. Evidently, therefore, immunological pathways that generate antigen binding Igs do not favor the synthesis of anti-SAg catalytic Igs.
Binding of conventional antigens to the BCR drives B cell division. BCR-catalyzed gp120 cleavage will result in release of the gp120 fragments, depriving the cells of the proliferative signal. In the conventional immune response, therefore, the catalytic activity can improve adaptively only to the extent that product release is slower than the proliferative transmembrane signal. IgAs/IgMs display superior proteolytic activity compared to IgGs. This is understandable if µ/α-BCRs generate more rapid transmembrane signals compared to γ-BCRs, a hypothesis that remains to be tested experimentally. A second scenario is that BCR catalysis itself induces cell proliferation. Peptide bond hydrolysis is highly exothermic and liberates large amount of energy. In theory, the catalytic energy could be utilized to induce favorable BCR signaling, e.g., by inducing a productive change in the BCR conformation or by increasing BCR diffusion in the lipid bilayer, thus increasing the probability of BCR cross-linking. Theoretically, BCR engagement by conventional antigens and SAgs could result in opposite cellular signaling, in that BCR catalyzed SAg hydrolysis and product release may lessen the down-regulatory and apoptotic effects of prolonged BCR occupancy by the SAg. Accordingly, adaptive maturation of B cells producing proteolytic Igs may be less restricted than of cells expressing BCRs that bind the SAg site stably.