Immunoglobulin-free light chains elicit immediate hypersensitivity-like responses

Redegeld, Frank A.; Heijden, M.W. van der; Kool, Mirjam; Heijdra, Bianca; Garssen, Johan; Kraneveld, Aletta D.; Loveren, Henk Van; Roholl, P. J. M.; Saito, Takashi; Verbeek, J. Sjef; Claassens, Jill; Koster, Andries S.; Nijkamp, Frans P.

doi:10.1038/nm722

Cited by 169 publications

(203 citation statements)

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“…Antigen-specific LCs were isolated from trinitrophenol (TNP)-(1B7-11, American Type Culture Collection) and oxazolone (OXA)-(NQ10͞12.5)-specific IgG (kindly provided by C. Milstein, Medical Research Council, Laboratory of Molecular Biology, Cambridge, U.K.) and purified as described (19,20). Recombinant LCs were produced by PCR cloning of cDNA 1B7-11 in a pGEX vector (Amersham Pharmacia Biosciences).…”

Section: Methodsmentioning

confidence: 99%

“…Recombinant LCs were produced by PCR cloning of cDNA 1B7-11 in a pGEX vector (Amersham Pharmacia Biosciences). Fusion proteins were expressed in Escherichia coli and purified by using affinity chromatography (19).…”

Section: Methodsmentioning

confidence: 99%

“…Our recent discovery that Ig free light chains (LCs) mediate antigen-specific mast cell-dependent hypersensitivity-like responses suggests that these molecules could be involved in the pathophysiology of adult asthma (19). We showed that mice, passively sensitized with antigen-specific LCs, when challenged by cutaneous exposure to the antigen, developed an allergic reaction characterized by mast cell-dependent plasma extravasation and tissue swelling (19).…”

mentioning

confidence: 99%

“…We showed that mice, passively sensitized with antigen-specific LCs, when challenged by cutaneous exposure to the antigen, developed an allergic reaction characterized by mast cell-dependent plasma extravasation and tissue swelling (19).…”

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confidence: 99%

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Elicitation of allergic asthma by immunoglobulin free light chains

Kraneveld

Kool

Houwelingen

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The observation that only 50% of patients with adult asthma manifest atopy indicates that other inflammatory mechanisms are likely involved in producing the characteristic features of this disorder; namely reversible airway obstruction, hyperresponsiveness, and pulmonary inflammation. Our recent discovery that antigen-specific Ig free light chains (LCs) mediate hypersensitivitylike responses suggests that these molecules may be of import in the pathophysiology of asthma. Using a murine experimental model of nonatopic asthma, we now have shown that an LC antagonist, the 9-mer peptide F991, can abrogate the development of airway obstruction, hyperresponsiveness, and pulmonary inflammation. Further, passive immunization with antigen-specific LCs and subsequent airway challenge can elicit a mast cell-dependent reaction leading to acute bronchoconstriction. These findings, and the demonstration that the concentration of free LCs in the sera of patients with adult asthma were significantly increased (as compared with age-matched nonasthmatic individuals), provide previously undescribed insight into the pathogenesis of asthma. In addition, the ability to inhibit pharmacologically LC-induced mast cell activation provides a therapeutic means to prevent or ameliorate the adverse bronchopulmonary manifestations of this incapacitating disorder.mast cells ͉ lung A sthma is a relatively common disorder manifested by airway inflammation that leads to bronchoconstriction and respiratory symptoms. Approximately 50% of adults with this disorder have atopic manifestations that involve IgE-mediated tissue sensitization with a T helper cell 2 response and eosinophilia (1, 2). However, that an equal percentage of patients with asthma are not atopic, as evidenced by negative skin-prick test as well as normal serum IgE levels and eosinophil counts (1, 2), indicates that other causative factors may be involved in the etiology of this disease. Furthermore, standardized comparisons across populations or time show only a weak and inconsistent association between the prevalence of adult asthma and the prevalence of atopy (1).Mast cells have been implicated as essential elements in the asthmatic process (3-5). Indeed, mast cell numbers are increased in the lungs of individuals with atopic as well as nonatopic variants of adult asthma, and the extent of degranulation of these cells is directly related to disease severity (6, 7). Although antigen-specific mast cell activation results from crosslinking of the high-affinity IgE receptor, FcRI, this effect can also occur in the absence of IgE antibodies (8-12); furthermore, anti-IgE antibody therapy has been of limited benefit in asthma (13-18).Our recent discovery that Ig free light chains (LCs) mediate antigen-specific mast cell-dependent hypersensitivity-like responses suggests that these molecules could be involved in the pathophysiology of adult asthma (19). We showed that mice, passively sensitized with antigen-specific LCs, when challenged by cutaneous exposure to the antigen, developed an...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Elicitation of allergic asthma by immunoglobulin free light chains

Kraneveld

Kool

Houwelingen

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…F991 is a 9-mer peptide derived from the amino-acid sequence in THP responsible for binding. 19 F991, a FLC antagonist, was synthesized as previously described 20 To investigate the effect of F991on viral myocarditis, 50 g of F991 dissolved in 0.5 mL of PBS was administered intraperitoneally immediately after EMCV inoculation and once daily until day 5. Control mice were given PBS.…”

Section: Effects Of Flc Antagonist On Experimental Myocarditismentioning

confidence: 99%