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Clin Exp Immunol. Mar 1998; 111(3): 521–526.
PMCID: PMC1904879

B cell-deficient mice do not develop type II collagen-induced arthritis (CIA)


To investigate the role of B cells in the development of CIA, a model for rheumatoid arthritis, we investigated susceptibility to CIA in mice lacking B cells due to the deletion of the IgM heavy chain gene (μMT). The μMT deletion was backcrossed into two different CIA-susceptible strains, B10.Q and B10.RIII. Two different variants of the CIA model are inducible in these strains: in B10.Q with rat type II collagen (CII) and in B10.RIII with bovine CII. Homozygous deletion of the IgM gene led to the absence of B cells and dramatically reduced immunoglobulin levels compared with wild-type mice. The deletion of IgM totally abrogated development of CIA in both strains, although the anti-CII T cell response did not differ between the μMT and wild-type controls. We conclude that B cells play a crucial role in the development of CIA.

Keywords: B cells, collagen-induced arthritis, autoimmunity, type II collagen


Rheumatoid arthritis (RA) is a severe and common disease, the pathogenesis of which is still little understood as regards its basic mechanisms. It is thought to be a tissue-specific autoimmune disease due to the fact that it involves a chronic inflammatory attack on peripheral joints, and classical forms of the disease are associated with HLA-DR genes [1]. Based on this hypothesis a search for autoantigenic specific T cells has been performed in many laboratories, with relatively meagre results. It has been possible to isolate T cells specific for type II collagen (CII), but these have been exceptions rather than rules [2]. On the other hand, local B cell activation to joint antigens has clearly been documented. B cells producing antibodies to CII occur early in the disease course and produce mainly IgG antibodies [3,4]. Interestingly, it has been reported that the local B cell response to CII is associated with HLA-DR4, thus reflecting a CII-specific T cell activation [5,6].

Other indirect support for a role of joint antigens in the development of arthritis is the induction of an arthritis after immunization of laboratory animals with CII (CIA) [7,8]. The development of CIA is similar to RA with regard to the spread of affected joints and the histopathology. In the rat a chronic disease course is seen, whereas in the mouse it is more self-limited [9]. The disease is clearly associated with the MHC region, and in mice only H-2r and H-2q haplotypes are susceptible [10]. The responsible gene in the H-2q haplotype has been isolated and codes for the Aq class II molecule [11]. This molecule binds peptides derived from CII, thus giving a structural explanation for the T cell activation which is of crucial importance for development of the arthritis. However, there are several unanswered questions in the CIA model which have bearings on RA. One question is how autoreactive T cells are triggered. As in RA, such T cells are difficult to isolate in CIA, and there is evidence for tolerization by physiological exposure to CII [12,13]. Another observation is the apparent lack of tolerization of autoreactive B cells specific for CII. A strong B cell response is activated in CIA, producing IgG directed towards CII-specific structures [14,15]. There is evidence that these antibodies are pathogenic, as exemplified by transfer experiments [16,17], and promote T cell-mediated arthritis development [18,19]. In contrast, levels of anti-CII autoantibodies in serum do not correlate with CIA development, as high levels can be detected in non-diseased mice [20,21]. Thus, the role of B cells in both the priming and effector phases of the disease is unclear.

By using B cell-deficient (μMT) mice of the strains B10.Q and B10.RIII we addressed the role of B cells in the induction of CIA. μMT−/− mice lack B cells due to disruption of the μ heavy chain transmembrane exon [22]. This disrupted exon-gene segment was backcrossed into the CIA-susceptible B10.Q and B10.RIII strains. Here we show that μMT mice are resistant to CIA induction, although the anti-CII T cell reactivity does not differ between B cell-deficient and B cell-sufficient mice. This indicates a crucial role for B cells in the induction of arthritis.



μMT in a cross of C57Bl/6×129 was kindly provided by Dr Werner Müller (Cologne, Germany); B10.Q and B10.RIII originate from Professor Jan Klein (Tübingen, Germany). μMT (C57Bl/6×129) mice were backcrossed to B10.Q (H-2q) mice for eight generations and then further intercrossed for two generations to provide homozygous B10.Q mice lacking B cells (μMT-BQ). H-2r-bearing mice were created by backcrossing heterozygous μMT-B10.Q (sixth generation) mice to B10.RIII for two generations and then further intercrossed for two additional generations to provide mice homozygous for both H-2r and μMT (μMT-BR). To select heterozygote μMT mice during the backcrossing to B10.Q and B10.RIII, DNA from the mice was investigated by polymerase chain reaction (PCR). The sequence of the 5′ primer was 5′-CTATTCGGCTATGACTGG-3′ (Neo3) and the 3′ was 5′-CCCCACAACCATACTACC-3′ (MT2). To provide heterozygous H-2r mice after the backcross to B10.RIII, a 5′ primer with the sequence 5′-ATTTCGTGGCCCAGTTGA-3′ (OAq5) and a 3′ primer with the sequence 5′-CCGCAGGGAGGTGTGGGT-3′ (OAq8) were used. All the offspring were investigated for absence of B cells by cytofluorimetric analyses before immunization. Male mice of each strain at 8–12 weeks old were immunized. All mice were kept and bred in the Animal Unit of Medical Inflammation Research (Lund University, Lund), an environmentally controlled and specific pathogen-free (SPF) facility.

FACS analysis

For screening for presence of B cells, in order to determine offspring homozygous for the μMT transgene, blood cells were stained with anti-B220 antibody labelled with Tri-Colour (Caltag, San Francisco, CA) before being analysed by FACScan (Becton Dickinson, Nutley, NJ).

For quantification of CD4+ and CD8+ T cells in μMT and wild-type mice, single-cell suspensions prepared for T cell proliferation assays (see below) were analysed. The cells were stained with PE-anti-CD4 (L3T4) antibody (Pharmingen, Los Angeles, CA), FITC-anti-Ly-2 (CD8a) antibody and Tri-Colour anti-CD45R (B220) antibody (Caltag).


Rat type II collagen (RCII) from a rat chondrosarcoma and bovine type II collagen (BCII) from calf joint cartilage were prepared by pepsin digestion and purification as described previously [23,24]. Both preparations of CII were stored lyophilized and dissolved in 0.1 m acetic acid (at 4°C) at least 24 h before use.

Induction and evaluation of arthritis

B10.Q mice and μMT-BQ male mice were immunized with 100 μg RCII in Freund's complete adjuvant (FCA; Difco, Detroit, MI) intradermally at the base of the tail and 35 days after immunization the mice were boosted at the same location with 50 μg RCII in Freund's incomplete adjuvant (FIA; Difco). For immunization of μMT-BR and B10.RIII male mice, 100 μg BCII in FCA were used and no booster injection was required. The mice were observed for development of arthritis starting from day 18 post-immunization and bled for anti-CII antibody determination at day 34 (B10.RIII strains) or day 48 (B10.Q strains). The clinical severity of arthritis was quantified according to a scoring system: 1 = swelling in one joint, 2 = swelling in more than one joint, 3 = severe swelling of the entire paw and/or ankylosis. Each paw was graded, so each mouse could achieve a maximum score of 12. In Table 1 the mean of the maximal score obtained from each diseased mouse within a group is indicated.

Table 1
Frequency of CIA and anti-collagen type II (CII) antibody titre after immunization with CII/Freund's complete adjuvant (FCA)

T cell proliferation assay

For T cell proliferation assays and FACS analysis male mice were immunized with RCII or BCII emulsified in FCA or H37Ra (Difco; 1 mg/ml) and injected intradermally in both hind footpads (50 μl), the neck (50 μl) and at the base of the tail (50 μl). Cervical, inguinal, popliteal, brachial and axillar lymph nodes from the immunized mice were obtained 11 days after immunization. Denatured CII, purified protein derivative (PPD; Statens Serum Institute, Copenhagen, Denmark) and the peptides rat CII256-270 [25] and bovine CII607-621 [26] were used as antigens in the cultures.


For the ELISA, Immunolon II microtitre plates (Dynatech, Chantilly, VA) were used. All the incubation steps were performed at room temperature except for the coating step, which was performed at 4°C overnight.

For analysis of interferon-gamma (IFN-γ) production, male mice were immunized with native RCII or BCII (2 mg/ml), emulsified with an equal volume of H37Ra (Difco) and injected intradermally in both hind footpads (50 μl) and at the base of the tail (50 μl). After 11 days single-cell suspensions from pooled inguinal and popliteal lymph nodes from the immunized mice μMT-BR, B10.RIII, μMT-BQ and B10.Q, respectively, were made. The single-cell suspensions (10 × 106 cells/well) were cultured in 24-well plates (Falcon, Beckton Dickinson Labware, Nutley, NJ) with denatured CII. After 72 h, the supernatants were collected and transferred to plates coated with 5 μg/ml of the MoAb R4-6 A2. Biotinylated MoAb An18 (50 ng/ml, 50 μl/well), extraAvidin conjugated with alkaline phosphatase (1 μg/ml; Sigma, St Louis, MO) and p-nitrophenyl phosphate (Sigma) were used to determine the amount of bound IFN-γ. Both anti-IFN-γ hybridomas were kindly provided by Dr Anne O'Garra (DNAX, Palo Alto, CA). Mouse recombinant IFN-γ (Genzyme, Cambridge, MA) was used as a standard. The plates were read at 405 nm.

For quantification of anti-CII antibodies in serum, plates were coated with native CII as previously described [24]. A mix of sheep anti-mouse IgG Fc and goat anti-mouse IgM, both conjugated with alkaline phosphatase (Jackson, West Grove, PA) and p-nitrophenyl phosphate, was used to determine the serum levels of anti-CII antibodies. For measuring total immunoglobulin levels in serum, plates were coated with goat anti-mouse IgG + IgM (Jackson) and then processed with the same detecting reagents as for quantification of anti-CII-specific antibody.


B cell-deficient mice do not develop CIA

By using two different mouse strains developing different variants of the CIA model, the B10.RIII mouse induced with BCII and associated with the H-2r haplotype, and the B10.Q strain induced with RCII and associated with the H-2q haplotype, the role of B cells was investigated. After immunization with CII, 100% of the B cell-sufficient B10.RIII mice and 88% of the B cell-sufficient B10.Q mice, but none of the B cell-deficient mice, developed arthritis (Table 1,Fig. 1). B10.RIII mice developed a rapid and severe disease with high serum levels of anti-CII antibodies, while B10.Q mice immunized with RCII developed a milder disease after a booster injection at day 35. As expected, B cell-deficient mice had no antibody response to CII (Table 1), although B cell-deficient offspring from heterozygous (μMT+/−) mothers had detectable levels of IgG antibodies in serum which remained for more than 8 months after birth (data not shown).

Fig. 1
The clinical development of CIA in B cell-deficient (μMT) ([filled square]) and B cell-sufficient mice (□). (a) μMT-BR (n = 5) and B10.RIII (n = 6). (b) μMT-BQ (n = 8) and B10.Q (n = 8) mice.

The anti-T cell response to CII is not altered in B cell-deficient mice

In order to explain the lack of CIA in B cell-deficient mice the T cell response to CII was investigated by analysing CII-specific T cell proliferation and IFN-γ production in vitro (Fig. 2). No significant differences in proliferative T cell responses to CII or to the immunodominant peptide bCII607-621 in BCII and rCII256-270 in RCII were noticed in the μMT CIA-resistant strains compared with the B cell-sufficient CIA-susceptible strains when FCA was used as adjuvant. When H37Ra was used as adjuvant there was a higher response in the B cell-deficient strain compared with the susceptible strains.

Fig. 2
Undisturbed T cell proliferation in B cell-deficient (μMT) compared with B cell-sufficient mice. The μMT-BQ (n = 3) and B10.Q (n = 3) mice were immunized with rat CII (RCII)/H37Ra, while the μMT-BR (n = 3) and B10.RIII (n = 3) ...

The effector function of CII-specific T cells was investigated by quantification in ELISA of IFN-γ production in cell culture supernatants (Fig. 3). Single-cell suspensions from draining lymph nodes (LN) were restimulated 11 days after immunization with 100 μg/ml CII in culture for 72 h. The ELISA quantification of culture supernatants showed no significant difference in IFN-γ production between B cell-deficient strains and their corresponding B cell-sufficient strain, in agreement with the anti-CII T cell proliferation results.

Fig. 3
No difference in CII-induced T cell production of IFN-γ. T cells from draining lymph nodes from μMT-BQ (n = 3) and B10.Q (n = 3) mice immunized with rat CII (RCII)/H37Ra and μMT-BR (n = 3) and B10.RIII (n = 3) immunized with bovine ...

One difference in T cell populations found in B cell-deficient mice was a relatively increased CD8+ T cell population in immunized LN, analysed by FACS. The mean CD4+/CD8+ cell ratio was 1.9 in μMT-BQ compared with 4.1 in normal B10.Q (Fig. 4) and 1.0 in μMT-BR compared with 2.2 in normal B10.RIII mice (data not shown). Besides an increase in the CD8+ population, there was also a four-fold increase in double-positive T cells.

Fig. 4
Flow cytometric analysis of lymph node (LN) T cells from μMT-BQ (a) and B10.Q (b) mice. Newly prepared LN cells from the cell suspensions used for proliferation studies in Fig. 2 were stained with PE-conjugated anti-CD4 antibody and FITC-conjugated ...


The finding that B cell-deficient mice are resistant to CIA is consistent with the large amount of circumstantial evidence suggesting a crucial role for B cells in CIA. It is possible to induce arthritis using serum containing anti-CII antibodies [17], although it has been more difficult to induce arthritis with MoAbs. While many IgG anti-CII antibodies do not induce arthritis, others do [27], and the differences have not yet been clarified. Experiments involving depletion of B cells have been reported whereby injection of high levels of rabbit anti-IgM antibody to rat neonates protected them from CIA later in life [28]. This treatment, however, not only decreases the number of B cells but will also modulate the entire immune system. This becomes obvious when the results of B cell-deficient animals obtained by neonatal anti-IgM treatment, which are resistant to experimental autoimmune encephalomyelitis (EAE) [29], are compared with the more recently published experiments using B cell-deficient mice, which are susceptible to EAE [30]. Experiments have also been performed by depleting different complement factors by cobra venom factor treatment [31] or with antibodies to C5 [32]. These experiments clearly show a role for complement in CIA pathology, but do not directly address the role of the B cell. Complement is clearly of importance not only in the inflammatory response but also for the priming of lymphocytes [33]. Genetic defects giving more specific B cell dysfunction have been reported to abrogate development of CIA. For instance, the X-linked immunodeficiency caused by a mutation in the btk gene [34,35] has been bred into the CIA-susceptible DBA/1 strain. These DBA/1-xid mice are resistant to CIA, but in these experiments a role for other X-linked genes cannot be excluded. In fact, reciprocal crosses shown in the same report indicated the presence of such genes [36]. Another gene defect stimulating B cells, the yaa gene located on the Y chromosome, also decreases CIA susceptibility [37], but in this case the specific dysfunction of the B cells is not yet known. In the present study analysing the influence of the μMT mutation, we cannot formally exclude a role for a gene of 129 origin linked to the Igh locus and bred into the CIA-susceptible strains. This is, however, highly unlikely, since such a locus is not found in genetically analysed crosses involving the B10.Q and B10.RIII mice (manuscripts in preparation). Thus, the present study clearly shows that B cells are necessary for development of CIA.

The CIA model is therefore different from a number of other models of autoimmune disease in which B cell-deficient mice do develop disease, albeit in some cases with a lower severity [30]. Furthermore, T cell-dependent immune functions such as tolerance induction [38], DTH [39] and antigen presentation [40] appear to function normally in the absence of B cells. In the present study we can confirm that the T cell responses, as measured by CII-induced proliferative activity (Fig. 2) and IFN-γ secretion (Fig. 3), were undisturbed. The higher T cell response when H37Ra was used as adjuvant could be explained by a higher fraction of T cells in cultures from B cell-deficient mice. However, the T cell response is mainly directed towards heterologous CII and might therefore not be directly relevant for the disease process. One difference found in B cell-deficient mice was a relatively increased CD8+ T cell population in immunized lymph nodes (Fig. 4). Besides an increase in the CD8+ population there was also a four-fold increase in double-positive T cells. Since these phenomena were identical between the strains, it is probably due to the lack of B cells. However, the high ratio of CD8+ T cells is unlikely to be the cause of unresponsiveness to CIA induction, since DBA/1 mice lacking CD4+ T cells and thereby having a high proportion of CD8+ cells are susceptible to CIA [41]. Another notable observation was that both μMT-BR and μMT-BQ offspring from heterozygous mothers still had detectable amounts of IgG at 8 months of age.

Why are B cells important for development of CIA? In our view this is due to a split tolerance in the immune response to CII. T cells specific for CII are tolerized by CII derived from cartilage, whereas CII-specific B cells can be activated to produce pathogenic antibodies. In a simplified scenario the immunization with heterologous CII, e.g. rat CII, will lead to activation of heteroreactive T cells which will promote the activation of autoreactive B cells producing pathogenic anti-CII autoantibodies. However, this scenario is probably too simple and raises a number of questions. The decisive event leading to the outbreak of arthritis and the self-perpetuating mechanisms leading to chronic arthritis cannot be explained solely by pathogenic antibodies. It is likely that autoreactive T cells are activated which permit a macrophage-mediated chronic destruction of the joints. The B cells may not only play a role as producers of pathogenic antibodies, but may also enhance antigen uptake and thereby macrophage activation and antigen presentation leading to a lowered threshold for the activation of T cells specific for autologous CII or other cartilage antigens. The μMT mice will be useful for solving this and other questions of great importance to the understanding of the mechanisms involved in the development of autoimmune arthritis.


This work was supported by the Swedish Medical Research Council, the Swedish Rheumatism Association, King Gustaf V's 80 year Foundation, Nanna Svartz Foundation, Crafoord Foundation, Alfred Österlund Foundation, Greta and Johan Kock Foundation, Börje Dahlin Foundation, Åke Wiberg Foundation and Anna-Greta Crafoord Foundation. We are grateful to Lennart Lindström and Yvette Sjöö for excellent care of the mice and for skilful technical assistance. We also want to thank Dr Andrew Cook for linguistic corrections of the manuscript, and Mikael Vestberg for FACS methodology.


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