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Yiping Zhang

Publications and source records attributed to Yiping Zhang.

At least 19 recordsLinked to original sources
PubMed2026

Ifebemtinib plus garsorasib in previously treated metastatic colorectal cancer with KRASG12C mutation: a multicentre, randomised, phase 1b/2 trial.

BACKGROUND: Ifebemtinib is a potent oral focal adhesion kinase inhibitor. Preclinical evidence supports combining ifebemtinib with the KRASG12C inhibitor garsorasib. This study aimed to evaluate this combination in KRASG12C-mutated solid tumours. METHODS: This multicentre, phase 1b/2 study had a phase 1b component to establish the recommended phase 2 dose and a phase 2 multitumour expansion component. In phase 1b, the safety and tolerability of ifebemtinib combined with garsorasib was assessed using a 3 + 3 design in KRASG12C-mutated solid tumours. No dose-limiting toxic effects were observed, and the recommended phase 2 dose was established as ifebemtinib 100 mg orally once daily plus garsorasib 600 mg orally twice daily. Here, we report the results of the cohort of previously treated KRASG12C-mutated metastatic colorectal cancer from phase 2 expansion. Eligible patients (aged ≥18 years) who had histologically confirmed locally advanced or metastatic colorectal cancer harbouring the KRASG12C mutation, an Eastern Cooperative Oncology Group performance-status score of 0 or 1, and had disease progression after previous irinotecan-based or oxaliplatin-based combination therapy, were recruited from seven of nine participating tertiary hospitals in China. On the basis of the recommended phase 2 dose, phase 2 comprised a single-arm study to evaluate the safety and efficacy of ifebemtinib combined with garsorasib and an open-label, randomised study in which patients were randomly assigned (1:1) to receive ifebemtinib plus garsorasib or garsorasib alone, by use of centralised computer-generated block randomisation with no stratification. Investigators were masked to the block size. The primary efficacy endpoint of phase 2 was investigator-assessed objective response rate (Response Evaluation Criteria in Solid Tumours, version 1.1), assessed in the safety analysis set in the single-arm study and in all randomly assigned patients (intention-to-treat population) in the randomised study. At least six objective responses (safety analysis set) were required in the single-arm study to proceed to the randomised study. This study is registered with ClinicalTrials.gov, NCT06166836 and NCT05379946, and is active but not recruiting. FINDINGS: Between April 7, 2023 and Dec 13, 2024, 51 patients were enrolled in phase 2 (15 in the single-arm study and 36 in the randomised study). In the single-arm study, the median age was 53 years (IQR 39 to 63), nine (60%) patients were female, six (40%) were male, and all were Asian. In the randomised study, the median age was 51 years (IQR 42 to 59) in the combination group and 63 years (IQR 54 to 66) in the monotherapy group, 24 (67%) were female, 12 (33%) were male, and all patients were Asian. In the single-arm part, the confirmed objective response rate was 46·7% (95% CI 21·3 to 73·4). Seven patients had partial responses, triggering progression to the randomised study. In the randomised study, the confirmed objective response rate was 38·9% (95% CI 17·3 to 64·3) with the combination therapy versus 16·7% (95% CI 3·6 to 41·4) with garsorasib alone (between-group difference 22·2%, 95% CI -7·7 to 49·1; one-sided p=0·068). In the single-arm study, grade 3 treatment-related adverse events occurred in four (27%) of 15 patients, and in the randomised study, grade 3 treatment-related adverse events occurred in six (33%) of 18 patients in the combination group and five (28%) of 18 in the garsorasib group. Grade 3 treatment-related adverse events occurring in at least two patients were diarrhoea (six [18%]), proteinuria (two [6%]), and intestinal obstruction (two [6%]) in patients treated with combination therapy (combined), and increased alanine aminotransferase and γ-glutamyltransferase (two [11%] each) in patients treated with garsorasib alone. Serious adverse events occurred in ten (30%) patients in the combination group and in four (22%) patients in the monotherapy group. One patient in the garsorasib monotherapy group died due to the underlying malignancy within 30 days after completing study treatment, which was reported as a serious adverse event. The death was assessed by the investigators as not related to garsorasib. No grade 4 treatment-related adverse events or treatment-related deaths were reported across all cohorts. INTERPRETATION: The combination of ifebemtinib and garsorasib showed promising anticancer activity and manageable safety profile in previously treated patients with KRASG12C-mutated metastatic colorectal cancer. Although the improvement in response rate did not reach statistical significance in the randomised study, these findings support further evaluation of ifebemtinib plus garsorasib in this population. FUNDING: InxMed, InventisBio, National Natural Science Foundation of China, the Jian Bing Ling Yan + X Research and Development Program of Zhejiang Province, and the Zhejiang Province Medical and Health Science and Technology Plan Project.

Humans↗
PubMed2007

B cell clonal expansion and somatic hypermutation of Ig variable heavy chain genes in the synovial membrane of patients with osteoarthritis.

Inflammatory mediators have been explored as possible factors in the initiation and/or progression of osteoarthritis (OA). This study shows that synovial infiltration by B lymphocytes is present in almost half of the knee OA cases. The degree of B lymphocyte infiltration is associated with more pronounced synovial inflammation and with the presence of plasma cells and lymphoid follicles in more severe cases. To examine whether these B cells are merely bystanders or could be involved in the pathogenesis of OA, we analyzed the Ig H chain variable region (V(H)) genes of B cells recovered from the synovial membrane of five OA patients with marked B cell infiltration. Sequence analysis of CDR3 regions of rearranged VDJ genes revealed clonal or oligoclonal B cell expansions in all cases. Expanded B cell clones in four of five OA patients showed clustered somatic mutations, occurring mainly in the CDRs and with a high replacement-to-silent ratio (>2.9), indicating that these cells are postgerminal center B cells that had been positively selected through their Ag receptor. These data demonstrate the presence in inflamed knee OA synovium of clonally expanded, Ag-driven B cells that may contribute to the development or progression of the disease.

Aged↗
PubMed2006

Triosephosphate isomerase- and glyceraldehyde-3-phosphate dehydrogenase-reactive autoantibodies in the cerebrospinal fluid of patients with multiple sclerosis.

Our previous results revealed that Igs in lesions and single chain variable fragment Abs (scFv-Abs) generated from clonal B cells in the cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) bind to axons in MS brains. To study the axonal Ags involved in MS, we identified the glycolytic enzymes, triosephosphate isomerase (TPI) and GAPDH, using Igs from the CSF and scFv-Abs generated from clonal B cells in the CSF and in lesions from MS patients. Elevated levels of CSF-Abs to TPI were observed in patients with MS (46%), clinically isolated syndrome (CIS) suggestive of MS (40%), other inflammatory neurological diseases (OIND; 29%), and other noninflammatory neurological diseases (ONIND; 31%). Levels of GAPDH-reactive Abs were elevated in MS patients (60%), in patients with CIS (10%), OIND (14%), and ONIND (8%). The coexistence of both autoantibodies was detected in 10 MS patients (29%), and 1 CIS patient (3%), but not in patients with OIND/ONIND. Two scFv-Abs generated from the CSF and from lesions of a MS brain showed immunoreactivity to TPI and GAPDH, respectively. The findings suggest that TPI and GAPDH may be candidate Ags for an autoimmune response to neurons and axons in MS.

Adult↗
PubMed2006

Genomewide scans in North American families reveal genetic linkage of essential tremor to a region on chromosome 6p23.

Essential tremor (ET) is the most prevalent adult-onset movement disorder showing evidence of non-random accumulation in some families. ET has previously been mapped to genetic loci on chromosomes 2p and 3q, but no causative genes identified. We conducted genomewide linkage screening with subsequent fine mapping in seven large North American families comprising a total of 325 genotyped individuals that included 65 patients diagnosed as definite ET. Linkage analysis was based on methodology implemented in SimWalk2 and LINKAGE programs. A multigenerational family revealed suggestive linkage to a locus on chromosome 6p23 with maximal nonparametric linkage (NPL) multipoint score 3.281 (P = 0.0005) and parametric multipoint log of the odds (LOD) score 2.983. A second family showed positive linkage to the same 6p23 region with a maximal NPL score 2.125 (P = 0.0075) and LOD score 1.265. Haplotype analysis led to the identification of a 600 kb interval shared by both families. Sequencing of coding regions of 15 genes located in the linked region detected numerous sequence variants, some of them predicting a change of the encoded amino acid, but each was also found in controls. Our findings provide evidence for linkage to a novel susceptibility locus on chromosome 6p23. Analysis of additional ET-affected families is needed to confirm linkage and identify the underlying gene.

Adult↗
PubMed2006

[Temporal-spatial characteristics of wind in tropical seasonal rainforest in Xishuangbanna of Yunnan Province].

Based on the observation data of wind speed and wind direction at different heights on the observation tower (70 m) in the tropical seasonal rainforest of Xishuangbanna, this paper analyzed the annual, seasonal and diurnal characteristics of wind. The results showed that the wind speed above crown canopy was stronger than that under canopy, and the diurnal and vertical change under the canopy was not obvious. From the height of 30 m to 50 m, the vertical change of wind speed was most remarkable, but its annual change was not obvious. Above 50 m, the change trend was opposite. Dry-hot season (March-April) had the strongest wind speed, followed by rainy season (May-October) and foggy-cool season (November -next February). The wind speed at daytime was stronger than that at nighttime. At daytime, wind speed was in order of morning > afternoon > noon. Wind direction had obvious diurnal characteristics, i. e., leaning southeast wind at daytime and leaning west wind at nighttime. At daytime, the change trend of zero-plane displacement (d) was in order of morning > noon > afternoon, and the annual change range in the afternoon was wider and lower than that in the morning and at noon. The change trend of roughness length (Z0) at daytime was opposite to that of d. The d value in the afternoon was obviously higher than that in the morning and at noon.

China↗
PubMed2006

[Physiology and ecology of Pometia tomentosa photosynthesis in tropical seasonal rain forest].

Pometia tomentosa is a dominant uppermost canopy tree in Xishuangbanna tropical seasonal rain forest. In this paper, the photosynthetic characteristics of the three layers of P. tomentosa canopy were measured with Li-6400 portable photosynthesis system, and the results showed that P. tomentosa had the characteristics of high light saturation point (1 000 - 1 500 micromol x m(-2) x s(-1)) and low compensation point (7.7 - 15.3 micromol x m(-2) x s(-1)). Its leaf photosynthesis had the adaptive responses when the high irradiance changed. PAR was the main factor affecting the diurnal changes of net photosynthesis. In December, the leaf grew well, and had a high ability of photosynthesis, with the diurnal change of P. for upper layer exhibiting single-peaked pattern and the maximum value being 8.9 micromol CO2 x m(-2) x s(-1). April was the alternative period of old and young leaves, and the ability of photosynthesis was dropped, with the diurnal change of P(n) for upper layer following double-peaked curve and the maximum value being 4.3 micromol CO2 x m(-2) x s(-1). The highest net photosynthesis rate was observed in July, with the diurnal change of P. for upper and middle layers exhibiting single-peaked pattern and that for lower layers being double-peaked. Short-term enriched CO2 concentration could evidently increase the photosynthesis of P. tomentosa, while the stomatic conductance and transpiration would be inhibited. When the CO, concentration increased from 400 micromol x mol(-1) to 800 micromol x mol(-1), water use efficiency (WUE) was increased by 50% - 100% in dry season, but rather low in wet season.

Adaptation, Physiological↗
PubMed2006

[Canopy rainfall storage capacity of tropical seasonal rainforest and rubber plantation in Xishuangbanna].

Based on the 2003-2004 laboratory and field observation data, and with scaling-up method, this paper studied the canopy rainfall storage capacity of tropical seasonal rainforest and rubber plantation in Xishuangbanna. The results showed that the canopy rainfall storage capacity was 0.45-0.79 mm for tropical seasonal rainforest and 0.48-0.71 mm for rubber plantation, and that of the branch and bark accounted for >50 % of the total. For these two forests, the canopy rainfall storage capacity was much higher in foggy season (from November to February) and dry-hot season (from March to April) than in rainy season (from May to October), and the duration needed to reach water saturation was about 5 min for leaf, 2-3 h for bark, and 2. 5-4 h for branch. During the processes of wetting and air-drying, leaf was easier while branch and bark were somewhat difficult to hold water and then be air-dried, suggesting that leaf played an important role in intercepting rainfall in short-duration rainfall events, while branch and bark could work much better in doing this in long-duration or high-intensity rainfall events. Compared with rubber plantation, tropical seasonal rainforest had a stronger rainfall-storage capacity due to its multi-layer structure of canopy and excellent water-holding performance.

China↗
PubMed2005

Axon reactive B cells clonally expanded in the cerebrospinal fluid of patients with multiple sclerosis.

Demyelination and axonal loss have been described as the histological hallmarks of inflammatory lesions of multiple sclerosis (MS) and are the pathological correlates of persistent disability. However, the immune mechanisms underlying axonal damage in MS remain unknown. Here, we report the use of single chain-variable domain fragments (scFv) from clonally expanded cerebrospinal fluid (CSF) B cells to show the role of an anti-axon immune response in the central nervous system (CNS) in MS. The cellular and subcellular distribution of the antigen(s) recognized by these CSF-derived clonal scFv antibodies (CSFC-scFv Abs) was studied by immunochemical staining of brain tissues obtained at autopsy from patients with MS. Immunochemistry showed specific binding of CSFC-scFv Abs to axons in acute MS lesions. The stained axons showed three major types of axonal pathological changes: 1) linear axons, axonal ovoid formation, and axonal transection were seen in the myelinated white matter adjacent to the lesion; 2) accumulation of axonal ovoid formations and Wallerian degeneration were seen at the border between demyelinated lesions and the adjacent white matter; and 3) Wallerian degeneration occurred at the center and edge of acute demyelinated lesions. These findings suggest a B cell axonal specific immune response in the CNS in MS.

Antigens↗
PubMed2005

Clonal expansion of IgA-positive plasma cells and axon-reactive antibodies in MS lesions.

Immunoglobulin A (IgA), the predominant immunoglobulin class in mucosal secretions, has been found in the cerebrospinal fluid of patients with multiple sclerosis (MS). In this study we examined the infiltration of clonally expanded IgA plasma cells in lesions of MS brains. Sequences of complementarity-determining region 3 of IgA variable heavy chain (V(H)) genes demonstrated the clonal expansion of IgA-bearing plasma cells in MS lesions. Somatic mutations and ongoing intra-clonal mutations occurred in their V(H) genes. Immunohistochemical study demonstrated infiltration of dimer and polymer IgA1- and A2-positive plasma cells in perivascular spaces, in the parenchyma of MS lesions, and in the adjacent white matter. Double immunofluorescence staining showed binding of IgA antibody on axons and walls of microvessels in the areas of chronic active and inactive demyelination. Bielshowsky's silver impregnation revealed axonal damage in these areas. These findings suggest that IgA in the CNS are localized on axons in lesions and may contribute to axonal damage in MS.

Antibodies↗
PubMed2005

[A comparison of various correction methods for calculating carbon flux above tropical seasonal rainforest].

In this paper, various correction methods were compared, based on the observation data of the CO2 and water fluxes above the canopy of a tropical seasonal rainforest in Xishuangbanna during 1-9 March, 2003. The results showed that it was necessary to correct the observation data when calculating the carbon flux, though various correction methods contributed differently to the results. For daytime data, WPL made the most important contribution, while sonic temperature correction did the least. t test indicated that no significant difference was found between the carbon fluxes corrected by WPL and the standard values. Cluster analysis showed that triple-rotation correction was helpful to improve the precision of the data. For nighttime data, it was the triple-rotation correction that made the most important contribution, and sonic temperature correction also did the least. There existed significant differences between the carbon fluxes corrected by WPL, planar-fit correction and their combination and the standard values, while the differences between the carbon fluxes corrected by double-or triple-rotation and the standard values were not significant. Cluster analysis showed that the data corrected orderly by coordinate axes-rotated correction and WPL would be propitious to improve the precision. The results would provide a basis for calculating the fluxes within tropical rainforest in the future, and supply reference to the fluxes calculation for other areas.

Atmosphere↗
PubMed2004

Link protein has greater affinity for versican than aggrecan.

The function of link protein in stabilizing the interaction between aggrecan and hyaluronan to form aggrecan aggregates, via the binding of link protein to the aggrecan G1 domain and hyaluronan, is well established. However, it is not known whether link protein can function with similar avidity with versican, another member of the large hyaluronan-binding proteoglycan family that also binds to hyaluronan via its G1 domain. To address this issue, we have compared the interaction of the versican and aggrecan G1 domains with link protein and hyaluronan using recombinant proteins expressed in insect cells and BIAcore analysis. The results showed that link protein could significantly improve the binding of both G1 domains to hyaluronan and that its interaction with VG1 is of a higher affinity than that with AG1. These observations suggest that link protein may function as a stabilizer of the interaction, not only between aggrecan and hyaluronan in cartilage, but also between versican and hyaluronan in many tissues.

Aggrecans↗
PubMed2004

Polyclonal B-cell expansion in the cerebrospinal fluid of patients with pseudotumor cerebri.

To investigate the hypothesis that pseudotumor cerebri (PTC) is associated with humoral immunity, we analyzed immunoglobulin heavy chain variable region (Ig-VH) genes of B cells in the cerebrospinal fluid (CSF) of 10 patients with PTC. Using RT-PCR and sequencing techniques, intrathecal B-cell Ig-VH genes were amplified in 6 of 10 PTC samples. Sequence analysis of complementarity-determining region 3 (CDR 3) and VH genes revealed a polyclonal intrathecal B-cell expansion in these patients. The nucleotide sequences showed that one-third of analyzed sequences had a high replacement to silent nucleotide substitution ratio, indicating an antigen-driven T-cell-dependent intrathecal B-cell proliferation. Moreover, other one-third had germline VH genes without or with a few nucleotide mutations, suggesting a T-cell-independent natural B-cell-mediated humoral immunity in the CNS of these patients. Our results suggest that both T-cell-dependent and T-cell-independent humoral immunity are present in the CSF of PTC.

Adolescent↗
PubMed2004

Molecular cloning and expression analysis of rice phosphoribulokinase gene that is regulated by environmental stresses.

Phosphoribulokinase (PRKase, EC 2.7.1.19) plays an important role in regulating the flow of sugar through the Calvin cycle. To investigate its regulatory character and expression pattern, the gene encoding PRKase in rice was cloned by RACE. A full-length cDNA with an open reading frame of 1212 bp encoding 403 amino acids residues was obtained from an indica rice variety, 9311. The OsPrk is a single locus gene in the rice genome. It is localized in the region of 28.32 approximately 28.33 Mb on the Chromosome 2, flanked by the genetic markers RM450 and MRG0168. RT-PCR analysis revealed that OsPrk gene was expressed in all the tissues we tested and OsPrk transcript level could be dramatically boosted by light illumination. Its expression was down-regulated by externally applied NaCl, ABA, MeJA and glucose over 24 hr, whereas it was up-regulated by GA after 24 hr treatments. These results also indicated that OsPrk gene expression is modulated by these factors at multiple levels.

Amino Acid Sequence↗
PubMed2004

[Influence of long-term fertilization on phosphorus fertility of calcareous soil I. Organic matter, total phosphorus and available phosphorus].

A 23 years-located experiment of wheat-corn rotation showed that long term application of animal manure combined with chemical fertilizer contributed greater to the contents of soil organic matter, total phosphorus, inorganic phosphorus and available phosphorus. Applying chemical fertilizer could increase soil organic matter, total phosphorus, inorganic phosphorus and available phosphorus contents, but the increment was lower than treatments animal manure and fallow. Compared with no fertilization, different fertilization treatment had its own distribution characteristics of soil organic matter, total phosphorus and available phosphorus in 0-100 cm soil layer.

Biomass↗
PubMed2004

[Radiation characteristics in a tropical seasonal rain forest canopy gap].

Based on the observations in the radiation with different wavelengths in tropical seasonal rain forest canopy gap, interior of forest, and meteorological station in different seasons, the radiation characteristics of canopy gap were discussed. The results showed that the value of different wavelength radiation had the phenomenon of "suddenly emergent" at the center and north edge of canopy gap. Moreover, each radiation value reached the maximum rapidly, and then decreased quickly around the noon. The daily gross radiation of different wavelengths within the canopy gap was bigger than that in the interior of forest, but smaller than that at meteorological station. Compared to the north edge, the daily gross radiation in the center of the gap was bigger in dry-hot season, rain season and later rain season, but smaller in fog-cool season, which was influenced by dense fog, solar angle and azimuth. The total daily gross solar radiation at the center was the maximum when the solar angle was the biggest in rain season, higher in later rain season and dry-hot season, and was the minimum in fog-cool season. The ratios of infrared and visible light radiation to total solar radiation varied with the seasons at the center and north edge of the canopy gap, which fully indicated the environmental heterogeneity within the canopy gap. Compared with meteorological station and interior of forest, the ratios of infrared radiation to total solar radiation in the gap were bigger than those of meteorological station, but smaller than those of interior of forest, which were just contrary to the ratios of visible light to total solar radiation. In addition, the seasonal variation of the ratios of visible light to total solar radiation was higher than that of the ratios of infrared radiation to total solar radiation within the gap. Generally, canopy gap could increase infrared radiation and decrease visible light radiation in tropical seasonal rainforest.

Environment↗
PubMed2003

Experimental immunity to the G1 domain of the proteoglycan versican induces spondylitis and sacroiliitis, of a kind seen in human spondylarthropathies.

OBJECTIVE: Experimental immunity to the G1 domain of the cartilage proteoglycan (PG) aggrecan (AG1) leads to the development of spondylitis as well as polyarthritis in BALB/c mice. The PG versican contains a structurally similar G1 domain (VG1). This study was conducted to determine whether immunity to VG1 would elicit similar pathology in these mice. METHODS: Recombinant natively folded VG1 and AG1 were prepared. BALB/c mice received either a series of 5 injections of human VG1 or AG1, or no protein. Polyarthritis was determined clinically, and spondylitis and sacroiliitis histologically. Immunohistochemistry of rat tissues was used to study the localization of versican. Enzyme-linked immunosorbent assays were employed to study humoral immunity to the recombinant proteins as well as to overlapping synthetic peptides covering all these human G1 domains and mouse homologs. Affinity-purified antibodies to human AG1 and VG1 were isolated from sera of hyperimmunized mice. T lymphocyte proliferation assays were performed using recombinant human proteins. T cell lines reactive with specific immunodominant T cell epitopes in human AG1 and VG1 were isolated. Synthetic peptides encoding sequences in these human proteins and in corresponding mouse proteins were used in these analyses. Guanidinium chloride extracts of mouse spines were also used in Western blots to study antibody cross-reactivity. RESULTS: Immunity to recombinant VG1 did not result in clinical polyarthritis. There was, however, clear evidence that VG1, like AG1, could induce spondylitis in the lumbar spine and sacroiliitis. Accumulation of mononuclear cells was observed in spinal ligaments adjacent to the intervertebral disc, in the intervertebral disc, and in the sacroiliac joints, the same sites where versican is localized. In contrast to AG1-immunized mice, in which T cells reactive with human AG1 cross-reacted with mouse AG1, there was no evidence in VG1-immunized mice that T cell immunity to human VG1 was cross-reactive with a mouse synthetic peptide that contained the sequence corresponding to the single immunodominant T cell sequence recognized in human VG1. Antibodies to specific sequences in human VG1 did, however, cross-react with human AG1 and with corresponding peptide sequences in mouse versican and aggrecan and with mouse proteins containing VG1 and AG1, present in mouse spine extracts. Similarly, antibodies to human AG1 cross-reacted with human VG1 and with extracted mouse VG1 and AG1 and synthetic peptides containing mouse sequences that corresponded to the reactive human epitopes in AG1 and VG1. CONCLUSION: These observations suggest that humoral immunity to human VG1 is involved in the induction of experimental spondylitis and sacroiliitis in BALB/c mice. This humoral immunity is cross-reactive with mouse versican and aggrecan but is not associated with polyarthritis, probably because of the lack of cross-reactive T cell immunity and the absence of detectable versican in articular cartilage limbs. Induction of polyarthritis by bovine or human aggrecan requires the involvement of immunity mediated by T lymphocytes that are cross-reactive to a mouse aggrecan epitope. Together these observations suggest that humoral immunity to versican as well as immunity to aggrecan may be of importance in the development of the spinal pathology characteristic of spondylarthropathies.

ADAM Proteins↗
PubMed2003

Animal models of inflammatory spinal and sacroiliac joint diseases.

Many cartilage matrix proteins or domains such as collagen types II, IX, and XI, GP39, AG1, VG1, and LP are potential antigens that might induce polyarthritis in susceptible animals (Table 1). Ordinarily, spondylitis is not a feature of polyarthritis induced with collagen types II, IX, and XI, GP39, cartilage matrix protein (matrilin-1) and cartilage LP. It seems that only the proteoglycans aggrecan and versican are capable of inducing sacroiliitis and spondylitis. Both molecules are structural proteins in intervertebral discs. Moreover, the arthritogenic or spondylitogenic epitopes of both molecules have been localized to the homologous N-terminal G1 globular domains. This region of versican and aggrecan is highly conserved, with 52% identity of amino acids. The homology is seen exclusively in the G1 domain and is concentrated between residues 115 and 332 (AG1 numbering) near the natural cleavage DIPEN site of aggrecan [84, 85]. Extra-articular pathology is often seen in rheumatic diseases, especially in AS. Other tissues, such as the sclera of the eye [86] and the media of the arteries [86, 87], also contain type II collagen, AG1, VG1, and LP, and versican is present in the central and peripheral nervous systems. Thus, there is the potential for an immune response against cartilage G1 and LP to be directed against related structures in extra-articular tissues. The presence of versican in the tendon and trochlea of the human superior oblique muscle might account for the occurrence of transient attacks of acquired Brown syndrome in patients with juvenile and adult forms of chronic RA [88]. Thus, it will be interesting to determine whether or not extra-articular expression of these cartilage proteins is closely related to extra-articular pathogenic expression in rheumatic diseases. Uveitis develops in VG1-immunized BALB/c mice, which is not seen in AG1-, and LP-treated animals. There is evidence that aggrecan and LP are also localized at these sites in the eye, but only immunity to versican can induce uveitis. In sacroiliitis and enthesitis of AS patients, the inflammation is associated with chondrometaplasia. In versican-induced sacroiliitis, replacement of cartilage by bone is seen with relatively little inflammation, somewhat resembling the situation in AS (Fig. 2). Versican can also stimulate chondrocyte proliferation [43]. Three conserved domains of human cartilage matrix molecules, namely VG1, AG1, and LP, show considerable homology [77, 79, 80, 89], and each is capable of inducing a unique inflammatory arthritis in BALB/c mice, with VG1 inducing only spondylitis [65], LP inducing peripheral arthritis with no spondylitis [90], and AG1 inducing axial and peripheral arthritis [66, 91]. It remains a mystery why such similar molecules cause different pathology in different target tissues. The exact immunopathogenic mechanisms deserve further study.

Amino Acid Sequence↗