Mold Odor from Wood Treated with Chlorophenols despite Mold Growth That Can Only Be Seen Using a Microscope.

We previously reported that indoor odorous chloroanisoles (CAs) are still being emitted due to microbial methylation of hazardous chlorophenols (CPs) present in legacy wood preservatives. Meanwhile, Swedish researchers reported that this malodor, described since the early 1970s, is caused by hazardous mold. Here, we examined to what extent CP-treated wood contains mold and if mold correlates with perceived odor. We found no studies in PubMed or Web of Science addressing this question. Further, we investigated two schools built in the 1960s with odor originating from crawlspaces. No visible mold was evident in the crawlspaces or on the surfaces of treated wood samples. Using a microscope, varying amounts of mold growth were detected on the samples, all containing both CP(s) and CA(s). Some samples smelled, and the odor correlated with the amount of mold growth. We conclude that superficial microscopic mold on treated wood suffices produced the odor. Further, we argue that CPs rather than mold could explain the health effects reported in epidemiological studies that use mold odor as an indicator of hazardous exposure.

Residential overcrowding in relation to children's health, environment and schooling - a qualitative study.

AIM: To explore how overcrowding affects children's health, environment and schooling. METHODS: A qualitative study was conducted with individual interviews among 20 participants with occupational experience from overcrowded Stockholm areas but diverse in professions, locations and employers. The interviews were recorded, transcribed and analysed with Systematic Text Condensation. RESULTS: Almost all participants expressed that overcrowding has a negative impact on children's health, environment and schooling - based on perceptions of precarious and different living conditions for children in overcrowded areas, for example, substandard homes, vulnerability, stress, exclusion, limited resources, lack of learning opportunities, gender differences, confinement, shame, insecurity, conflicts, risk of criminality, and bodily impact, both physical and psychological. CONCLUSIONS: Our qualitative evidence suggest that overcrowding has a negative impact on children's health, environment and schooling.

Overcrowding and Hazardous Dwelling Condition Characteristics: A Systematic Search and Scoping Review of Relevance for Health.

Crowding in dwellings is an important public health issue. We hypothesize that overcrowding may cause indirect health effects by adversely affecting the dwelling itself, for example, by increasing dampness leading to mold. We therefore performed a systematic search and a scoping review on overcrowding leading to dwelling condition characteristics of relevance for health. A literature search was performed using the PubMed and Scopus databases up to 5 March 2021. The search yielded 100 records with relevant information. We found that overcrowding is defined in numerous ways and often address "socially deprived" populations. Six studies report associations of overcrowding with at least one dwelling condition characteristic, namely lead, cadmium, microorganism distribution, dust mite and cockroach allergens in dust, cockroach infestation, peeling paint, and mold. One of the studies reports associations between several characteristics, e.g., association of mold with cleanliness and rodent infestation, and points out the common use of pesticides. Additional characteristics were extracted from the remaining 94 records, without data on statistical associations with overcrowding. Our review suggests that multiple potentially hazardous dwelling condition characteristics often coincide in overcrowded dwellings. The epidemiological attribution of health effects to any characteristic is therefore difficult. Causal relationships are even more difficult to establish, as overcrowding is also associated with a range of social and other circumstances that may affect health. The complexity should be considered by scientists and practitioners dealing with overcrowding in dwellings.

Chloroanisoles and Chlorophenols Explain Mold Odor but Their Impact on the Swedish Population Is Attributed to Dampness and Mold.

We recently reported that mold odor may be explained by chloroanisoles (CAs) formed by microbial biotransformation of chlorophenols (CPs) in legacy wood preservatives. Here we examine psychophysical aspects of CAs and trace their historic origins in buildings. Our exposure of healthy volunteers shows that 2,4,6-triCA is often perceived as unpleasant, characterized as musty or moldy and is detected at 13 ng/m3 or lower. Similar concentrations are reported in buildings with odor complaints. Scrutiny of written records reveal that new building construction methods were introduced in the 1950s, namely crawlspaces and concrete slabs on the ground. These constructions were prone to dampness and attack from wood decay fungi, prompting chemical companies and authorities to advocate preservatives against rot. Simultaneously, CPs became household chemicals used for example in indoor paints. When large-scale odor problems evolved, the authorities that once approved the preservatives attributed the odor to hidden mold, with no evidence that substantial microbial biomass was necessary for odor formation. Thereby the public remained unaware of problematic exposure to CPs and CAs. We conclude that the introduction of inappropriate designs of house foundations and CP-based preservatives once ignited and still provide impetus for indoor air research on "dampness and mold".

Acute effects of acrolein in human volunteers during controlled exposure.

CONTEXT: Acrolein is a reactive aldehyde mainly formed by combustion. The critical effect is considered to be irritation of the eyes and airways; however, the scarce data available make it difficult to assess effect levels. OBJECTIVE: The aim of the study was to determine thresholds for acute irritation for acrolein. METHODS: Nine healthy volunteers of each sex were exposed at six occasions for 2 h at rest to: clean air, 15 ppm ethyl acetate (EA), and 0.05 ppm and 0.1 ppm acrolein with and without EA (15 ppm) to mask the potential influence of odor. Symptoms related to irritation and central nervous system effects were rated on 100-mm Visual Analogue Scales. RESULTS: The ratings of eye irritation were slightly but significantly increased during exposure to acrolein in a dose-dependent manner (p < 0.001, Friedman test) with a median rating of 8 mm (corresponding to "hardly at all") at the 0.1 ppm condition and with no influence from EA. No significant exposure-related effects were found for pulmonary function, or nasal swelling, nor for markers of inflammation and coagulation in blood (IL-6, C-reactive protein, serum amyloid A, fibrinogen, factor VIII, von Willebrand factor, and Clara cell protein) or induced sputum (cell count, differential cell count, IL-6 and IL-8). Blink frequency recorded by electromyography was increased during exposure to 0.1 ppm acrolein alone but not during any of the other five exposure conditions. CONCLUSION: Based on subjective ratings, the present study showed minor eye irritation by exposure to 0.1 ppm acrolein.

Genetic variation influences immune responses in sensitive rats following exposure to TiO2 nanoparticles.

This study examines the immunological responses in rats following inhalation to titanium dioxide nanoparticles (TiO2 NPs), in naïve rats and in rats with induced allergic airway disease. The responses of two different inbred rat strains were compared: the Dark Aguoti (DA), susceptible to chronic inflammatory disorders, and the Brown Norwegian (BN), susceptible to atopic allergic inflammation. Naïve rats were exposed to an aerosol of TiO2 NPs once daily for 10 days. Another subset of rats was sensitized to the allergen ovalbumin (OVA) in order to induce airway inflammation. These sensitized rats were exposed to TiO2 NPs before and during the allergen challenge. Naïve rats exposed to TiO2 NPs developed an increase of neutrophils and lymphocytes in both rat strains. Airway hyperreactivity and production of inflammatory mediators typical of a T helper 1 type immune response were significantly increased, only in DA rats. Sensitization of the rats induced a prominent OVA-specific-IgE and IgG response in the BN rat while DA rats only showed an increased IgG response. Sensitized rats of both strains developed airway eosinophilia following allergen challenge, which declined upon exposure to TiO2 NPs. The level of neutrophils and lymphocytes increased upon exposure to TiO2 NPs in the airways of DA rats but remained unchanged in the airways of BN rats. In conclusion, the responses to TiO2 NPs were strain-dependent, indicating that genetics play a role in both immune and airway reactivity. DA rats were found to be higher responder compared to BN rats, both when it comes to responses in naïve and sensitized rats. The impact of genetically determined factors influencing the inflammatory reactions pinpoints the complexity of assessing health risks associated with nanoparticle exposures.

A 129-kb deletion on chromosome 12 confers substantial protection against rheumatoid arthritis, implicating the gene SLC2A3.

We describe a copy-number variant (CNV) for which deletion alleles confer a protective affect against rheumatoid arthritis (RA). This CNV reflects net unit deletions and expansions to a normal two-unit tandem duplication located on human chr12p13.31, a region with conserved synteny to the rat RA susceptibility quantitative trait loci Oia2. Genotyping, using the paralogue ratio test and SNP intensity data, in Swedish samples (2,403 cases, 1,269 controls) showed that the frequency of deletion variants is significantly lower in cases (P = 0.0012, OR = 0.442 [95%CI 0.258-0.755]). Reduced frequencies of deletion variants were also seen in replication materials comprising 9,201 UK samples (1,846 cases, 7,355 controls) and 2,963 US samples (906 controls, 1,967 cases) (Mantel-Haenszel P = 0.036, OR = 0.559 [95%CI 0.323-0.966]). Combining the three datasets produces a Mantel-Haenszel OR of 0.497 (P < 0.0002). The deletion variant lacks 129-kb of DNA containing SLC2A3, NANOGP1, and SLC2A14. SLC2A3 encodes a high-affinity glucose transporter important in the immune response and chondrocyte metabolism, both key aspects of RA pathogenesis. The large effect size of this association, its potential relevance to other diseases in which SLC2A3 is implicated, and the possibility of targeting drugs to inhibit SLC2A3, argue for further examination of the genetics and the biology of this CNV.

Strain differences influence timing and magnitude of both acute and late inflammatory reactions after intratracheal instillation of an alkylating agent in rats.

The acute pulmonary responses after exposure to sulfur and nitrogen mustards are well documented whereas the late pulmonary effects are not. With a novel focus on the immune system this paper investigate whether late phase pulmonary effects developed in rats exposed to the nitrogen mustard melphalan are linked to the acute responses and whether the reactions are genetically regulated. The DA rat strain was used to establish a lung exposure model. Five other inbred rat strains (PVG, PVG.1AV1, LEW, WF and F344) were compared within the model at selected time points. All rat strains displayed a biphasic pattern of leukocyte infiltration in the lungs, dominated by neutrophils 2 days after exposure and a second peak dominated by macrophages 29 days after exposure. The number of macrophages was higher in the DA rat compared with the other strains. The infiltration of lymphocytes in the lungs varied in both time of appearance and magnitude between strains. The quantity of collagen deposition in the lungs varied between strains at day 90; LEW and WF displayed high collagen content which coincided with an increased level of cytotoxic T cells. LEW further displayed an increased number of T helper cells and natural killer (NK) T cells in the lungs. The results in this study suggest there is a link between the development of lung fibrosis and high cytotoxic cell responses and that there is a genetic influence, as there are variations in acute and late adverse reactions between rat strains in both timing and magnitude.

Profound and paradoxical impact on arthritis and autoimmunity of the rat antigen-presenting lectin-like receptor complex.

OBJECTIVE: The antigen-presenting lectin-like receptor complex (APLEC) was recently identified as a genetic determinant for arthritis susceptibility. We undertook this study to define mechanisms underlying the impact of APLEC on arthritis, to determine whether sex effects occur, and to determine whether APLEC influences different types of arthritis and phenotypes other than susceptibility. METHODS: Arthritis-susceptible DA rats were compared with sex-matched congenic rats in which APLEC alleles were substituted with alleles from arthritis-resistant PVG rats. Six different arthritogenic agents were injected at the base of the tail: Freund's incomplete adjuvant, pristane, squalene, killed mycobacteria, yeast beta-glucan, or rat type II collagen (CII). Arthritis was visually scored, body weight was measured, and anti-CII IgG and cytokine messenger RNA (mRNA) levels were determined by enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction, respectively. RESULTS: In 5 models of rheumatoid arthritis (RA), congenic rats deviated profoundly from DA rats by having reduced arthritis susceptibility, delayed onset, decreased severity, and/or reduced body weight loss. Paradoxical opposite genetic effects were noted, including a more severe disease course in congenic males in pristane-induced arthritis and decreased clinical signs in collagen-induced arthritis despite increased autoantibody levels. Interestingly, the anti-CII IgG isotype profile was skewed in congenic rats, and markedly reduced lymph node mRNA levels for interleukin-17 suggested that the cytokine profile of autoreactive T helper cells was also skewed in a less pathogenic direction. CONCLUSION: Rat APLEC regulates autoimmunity and multiple phenotypes in several types of arthritis. However, delineating the genetic impact may require stratification for sex or mode of arthritis induction. This pathogenetic complexity should be considered when evaluating APLEC in inflammatory and autoimmune diseases, including RA.

Association of arthritis with a gene complex encoding C-type lectin-like receptors.

OBJECTIVE: To identify susceptibility genes in a rat model of rheumatoid arthritis (RA) and to determine whether the corresponding human genes are associated with RA. METHODS: Genes influencing oil-induced arthritis (OIA) were position mapped by comparing the susceptibility of inbred DA rats with that of DA rats carrying alleles derived from the arthritis-resistant PVG strain in chromosomal fragments overlapping the quantitative trait locus Oia2. Sequencing of gene complementary DNA (cDNA) and analysis of gene messenger RNA (mRNA) expression were performed to attempt to clone a causal gene. Associations with human RA were evaluated by genotyping single-nucleotide polymorphisms (SNPs) in the corresponding human genes and by analyzing frequencies of alleles and haplotypes in RA patients and age-, sex-, and area-matched healthy control subjects. RESULTS: Congenic DA rats were resistant to OIA when they carried PVG alleles for the antigen-presenting lectin-like receptor gene complex (APLEC), which encodes immunoregulatory C-type lectin-like receptors. Multiple differences in cDNA sequence and mRNA expression precluded cloning of a single causal gene. Five corresponding human APLEC genes were identified and targeted. The SNP rs1133104 in the dendritic cell immunoreceptor gene (DCIR), and a haplotype including that marker and 4 other SNPs in DCIR and its vicinity showed an indication of allelic association with susceptibility to RA in patients who were negative for antibodies to cyclic citrullinated peptide (anti-CCP), with respective odds ratios of 1.27 (95% confidence interval [95% CI] 1.06-1.52; uncorrected P = 0.0073) and 1.37 (95% CI 1.12-1.67; uncorrected P = 0.0019). Results of permutation testing supported this association of the haplotype with RA. CONCLUSION: Rat APLEC is associated with susceptibility to polyarthritis, and human APLEC and DCIR may be associated with susceptibility to anti-CCP-negative RA.

Resolution of a 16.8-Mb autoimmunity-regulating rat chromosome 4 region into multiple encephalomyelitis quantitative trait loci and evidence for epistasis.

To investigate effects of a 16.8-Mb region on rat chromosome 4q42-43 on encephalomyelitis, we performed a high-resolution mapping using a 10th generation advanced intercross line between the susceptible DA strain and the MHC identical but resistant PVG.1AV1 strain. Clinical signs of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) developed in 29% of 772 F(10) rats. Three regions controlling disease, Eae20, Eae21, and Eae22, were mapped using 15 microsatellite markers spanning 16.8 Mb. Eae20 was a major genetic determinant within the region whereas Eae21 modified disease severity. Eae22 was identified as an epistatic region because it only displayed an effect together with Piebald Virol Glaxo (PVG) alleles on Eae20. Disease down-regulation by PVG alleles in the telomeric part of Eae20 was also demonstrated in DA rats made congenic for a approximately 1.44-Mb chromosomal region from PVG. As the region containing Eae20-Eae22 also regulates arthritis, together with the fact that the syntenic mouse 6F(2)-F(3) region regulates experimental lupus and diabetes, and the syntenic human 12p13.31-13.2 region regulates multiple sclerosis and rheumatoid arthritis, the present data point to genes that control several inflammatory diseases. The pairscan analyses of interaction, which here identified Eae22, are novel in the encephalomyelitis field and of importance in the design of further studies of this region in other diseases and species. The limited number of genes identified in Eae20, Eae21, and Eae22 enables focused examination of their relevance in mechanistic animal studies and screening of their association to human diseases.

Identification of lectin-like receptors expressed by antigen presenting cells and neutrophils and their mapping to a novel gene complex.

In an experimental rat model, we recently mapped an arthritis susceptibility locus to the distal part of Chromosome 4 containing genes predicted to encode C-type lectin superfamily (CLSF) receptors. Here we report the cDNA cloning and positional arrangement of these receptor genes, which represent rat orthologues to human Mincle and DCIR and to mouse MCL and Dectin-2, as well as four novel receptors DCIR2, DCIR3, DCIR4 and DCAR1, not previously reported in other species. We furthermore report the cDNA cloning of human Dectin-2 and MCL, and of the mouse orthologues to the novel rat receptors. Similar to the killer-cell lectin-like receptors (KLR) some of these receptors exhibit structural features suggesting that they regulate leukocyte reactivity; e.g., human DCIR and rodent DCIR1 and DCIR2 carry an immunoreceptor tyrosine-based inhibitory motif (ITIM), predicting inhibitory function, and conversely, in all three species Mincle has a positively charged amino acid in the transmembrane region, suggesting activating function. Sequence comparisons show that the receptors form a discrete family, more closely related to group II CLSF receptors than to the group V KLR. Their distance to the KLR is underscored by their preservation of evolutionary conserved calcium/saccharide binding residues, present in group II and lacking in group V CLSF and their cellular expression patterns, with most of the genes preferentially expressed by professional antigen-presenting cells (dendritic cells, macrophages and B cells) and neutrophils. In all three species, the genes map together, forming an evolutionary conserved gene complex, which we call the antigen presenting lectin-like receptor complex (APLEC).

An advanced intercross line resolves Eae18 into two narrow quantitative trait loci syntenic to multiple sclerosis candidate loci.

Identification of polymorphic genes regulating inflammatory diseases may unravel crucial pathogenic mechanisms. Initial steps to map such genes using linkage analysis in F(2) intercross or backcross populations, however, result in broad quantitative trait loci (QTLs) containing hundreds of genes. In this study, an advanced intercross line in combination with congenic strains, was used to fine-map Eae18 on rat chromosome 10 in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE). Myelin oligodendrocyte glycoprotein-induced EAE is a chronic relapsing disease that closely mimics key features of multiple sclerosis. Congenic DA.ACI rat strains localized Eae18 to an approximately 30-Mb large region. Fine-mapping was then performed in an advanced intercross line consisting of a (DA x PVG.1AV1)F(7) intercross, resulting in two adjacent EAE-regulating QTLs designated Eae18a and Eae18b. The two QTLs span 5.5 and 3 Mb, respectively, and the 3-Mb Eae18b contains as few as 10 genes, including a cluster of chemokine genes (CCL1, CCL2, CCL7, and CCL11). Eae18a and Eae18b are syntenic to human chromosome 17p13 and 17q11, respectively, which both display linkage to multiple sclerosis. Thus, Eae18 consists of at least two EAE-regulating genes, providing additional evidence that clustering of disease-regulating genes in QTLs is an important phenomenon. The overlap between Eae18a and Eae18b with previously identified QTLs in humans and mice further supports the notion that susceptibility alleles in inflammatory disease are evolutionary conserved between species.

Oligodeoxynucleotides containing CpG motifs can induce T cell-dependent arthritis in rats.

OBJECTIVE: To investigate whether CpG oligodeoxynucleotides (ODNs) can induce or accelerate arthritis in rats. METHODS: The CpG-induced response was studied by recording joint inflammation, cell activation in draining lymph nodes, and levels of the acute-phase reactant alpha(1)-acid glycoprotein (AGP) in sera. The role of T cells was investigated by in vivo administration of monoclonal antibodies specific for the T cell receptor alpha/beta (TCRalpha/beta), followed by analysis of cell phenotypes by flow cytometry. RESULTS: One intradermal injection of CpG ODN emulsified with Freund's incomplete adjuvant (IFA) induced arthritis in LEW and LEW.1AV1 rats, while the control ODN sequence without CpG motifs or IFA alone did not trigger disease. The CpG/IFA and control-ODN/IFA injections induced lymphoplasia as well as elevated levels of interleukin-1beta and interferon-gamma messenger RNA in lymph nodes. The arthritis was preceded by elevated levels of AGP in serum. In vivo administration of anti-TCRalpha/beta antibodies after disease induction caused decreased expression of the TCR-CD3 complex on circulating T cells and ameliorated the arthritis. CONCLUSION: We demonstrated that injection with immunostimulatory CpG, both in phosphorothioate-modified and native forms, can induce a T cell-dependent joint-specific inflammation in LEW and LEW.1AV1 rat strains. This arthritis is preceded by signs of activation of the innate immune system. Since unmethylated CG dinucleotides are common in bacterial DNA but rare in mammalian DNA, our results indicate that exposure to bacterial DNA during infection may contribute to arthritis induction by amplifying the innate immune response.

High resolution mapping of an arthritis susceptibility locus on rat chromosome 4, and characterization of regulated phenotypes.

The rat Natural Killer cell gene Complex (NKC) encodes molecules that can regulate immunity. It is located within an interval on DA rat chromosome 4 (RNO4) that is linked to immune-mediated inflammatory joint diseases, including oil-induced arthritis (OIA). We aimed to test the hypothesis that NKC regulates arthritis, by performing advanced mapping of arthritis and additional phenotypes induced by an intradermal injection of incomplete Freund's adjuvant-oil. Reciprocal transfer of RNO4 intervals established that alleles from DA confer arthritis susceptibility to inbred LEW.1AV1 and PVG.1AV1 rats, whereas LEW.1AV1 and PVG.1AV1 alleles confer resistance to inbred DA. Subcongenic strains with PVG.1AV1 alleles introduced on DA allowed mapping of disease predisposition to 0.8 cM on the cytogenetic band 4q42, within the quantitative trait locus oil-induced arthritis-2 (Oia2), but outside the NKC. Alleles in Oia2 regulated arthritis in an additive fashion, and determined arthritis incidence, severity and day of onset, in both males and females. Besides macroscopic joint-inflammation, Oia2 also regulated other oil-induced phenotypes, including lymphoplasia and plasma levels of the inflammation marker alpha1-acid glycoprotein. The high-impact Oia2 region harbors gene sequences similar to human C3AR1, Ribosomal protein L7, DNAJA2, C-type lectins, C1s and CD163. These candidate disease genes may be of general interest, given that rat 4q42, and the syntenic mouse 6F2 and human 12p13 regions are linked to several inflammatory diseases, including rheumatoid arthritis.

Paradoxical effects of arthritis-regulating chromosome 4 regions on myelin oligodendrocyte glycoprotein-induced encephalomyelitis in congenic rats.

Immunoregulatory gene loci in different organ-specific inflammatory diseases often co-localize. We here studied myelin oligodendrocyte glycoprotein (MOG)-induced EAE in rat strains congenic for arthritis-regulating genome regions on chromosome 4. We used congenic rats with a 70-centimorgan (cM) fragment from the EAE- and arthritis-resistant PVG.1AV1 rat strain on the arthritis- and EAE-permissive Dark Agouti (DA) rat background. In addition, we evaluated three recombinant strains, C4R1-C4R3, which overlap with arthritis-linked loci. PVG.1AV1 alleles in the C4R1 recombinant did not affect arthritis, but conferred protection against MOG-EAE. PVG.1AV1 alleles in the C4R2 recombinant down-regulated arthritis but had no effect in MOG-EAE. Paradoxically, PVG.1AV1 alleles in the C4R3 recombinant down-regulated arthritis, but the same fragment increased serum levels of anti-MOG Ab and aggravated clinical MOG-EAE. Thus, we provide original evidence that the same genome regions can have opposite effects in different organ-specific inflammatory diseases. Interestingly, no apparent difference in the MOG-EAE phenotype was observed in full-length congenic rats and parental DA rats, suggesting that the disease amelioration in C4R1 and aggravation in C4R3 functionally counteract each other. The data set the stage for definition of the mechanisms and positioning of the genes regulating two organ-specific inflammatory diseases differently.

Mapping and functional characterization of rat chromosome 4 regions that regulate arthritis models and phenotypes in congenic strains.

OBJECTIVE: DA rats are highly susceptible to experimental models of rheumatoid arthritis (RA). Linkage analyses in different models have identified several quantitative trait loci (QTLs) within a 70-cM region of DA rat chromosome 4 (C4). We produced congenic strains for these QTLs in order to map and characterize their impact on arthritis development. METHODS: Selective breeding was used to transfer C4 intervals from arthritis-resistant PVG.1AV1 rats onto DA rats. These congenic strains were evaluated for susceptibility to arthritis induced by intradermal injection of rat type II collagen, pristane (a well-defined synthetic adjuvant oil), mycobacteria, or squalene (an endogenous adjuvant oil used in human vaccine). RESULTS: Rats congenic for PVG.1AV1 genes in the 70-cM region were less susceptible than DA rats to collagen-induced arthritis (CIA), pristane-induced arthritis, adjuvant-induced arthritis, and squalene-induced arthritis (SIA). Experiments in subcongenic strains indicated a gene regulating arthritis in males located in a 20-cM interval overlapping the QTL Pia5. A second gene, located in a 10-cM interval harboring the QTL Oia2, attenuated SIA and CIA. The latter caused a change in anticollagen antibody isotype levels toward a pattern similar to that seen in PVG.1AV1 rats. CONCLUSION: The QTL Oia2 regulates arthritis induced both by the nonimmunogenic immunostimulant squalene and by cartilage collagen. In CIA, it also skews anticollagen isotype profiles, suggesting qualitative regulation of autoimmunity. Interestingly, the homologous human chromosome region 12p12-p13 has also been linked to RA, suggesting that genetic and functional dissection of this locus will provide clues to disease pathways that lead to joint inflammation.