key: cord-0010626-h1e9u886
authors: HARALDSSON, Á.; JAMINON, M.; BAKKEREN, J.A.J.M.; STOELINGA, G. B. A.; WEEMAES, C. M. R.
title: Immunoglobulin G, A, and M Light Chain Ratios in some Humoral Immunological Disorders
date: 2006-06-29
journal: Scand J Immunol
DOI: 10.1111/j.1365-3083.1992.tb02940.x
sha: e2065cd811d09605dd3077efd83c86964dda6e30
doc_id: 10626
cord_uid: h1e9u886

The total kappa/lambda immunoglobulin light chain ratio and the kappa/lambda ratios within each of the serum immunoglobulin classes G. A. and M were measured in thirteen patients with humoral immunological disorders. Of those patients, eight had common variable immunodeficiency whereas live patients had other forms of humoral immunological deficiencies. Eleven patients had abnormal antibody response in vivo. All but three of the thirteen patients had clearly abnormal light chain ratios in one or more of the immunoglobulin classes. We conclude that humoral immunological disorders, usually characterized by abnormal heavy chain production and a disturbed antibody response, may frequently have a concomitant abnormal synthesis of the light chains resulting in an abnormal kappa/lambda light chain ratio.

The total immimoglobttlin kappa, lambda [K /.) light ehain ratio has been found to deviate from the tiormal in a variety of infectiotis diseases [l|. autoimtnune disorders [I 4] . and other itnmunoiogieal abnormalities [I. 5] . A Kjk light ehain imbalanee has also been described in some luimoral itnmune deficieneies, usually superimposed on an altered heavy chain produetion affeeting all or some of the immunoglobtilin classes [5. 6] . These studies have hitherto primarily been done on total K// ratio. As IgG usually represents the bulk of the tolal serutn itnmunoglobulins. the total }< '/. ratio refleets primarily the IgG K]'/. ratio.

Fight ehain restricted antibody responses whieh primarily contain either kappa-or lambdabearing immunoglobulins have been demonstrated Ibllowing stimulation by certain antigens [7 y ]. Some immunological disorders presenting with abnormal heavy ehain concentrations also have a defective antibody response [10] . The light chains have not been investigated in this context.

Recently methods have been deseribed for measuring not only total KI/. ratio but also polyelonal IgG, IgA. and IgM KI'/. ratios separ-ately [II. 12], encouraging further work on the issue. In addition, reference values for polyelona! IgG. IgA. and IgM ^ A ratios according to age arc known [13] .

In order to investigate a possible relationship between abnormal heavy and light chain production, K// ratios in IgG. IgA. and IgM as well as total K'l ratio were studied in patients with some hutnoral disorders. Abnormal light chain ratios in these palients might help explain the abnortnal antibody response found in vivo.

The lotal number of patients enrolled in the study was thirteen (Table I) . Fight patients had common variable immunodeficiency (CVID). two patients had immunodeficiency with hyper IgM and three patients had a lunctional antibody deficiency. Of those patients with functional antibody deficiency, one had antibody deficiency with normal immunoglobulin coneentralions. one had IgM deficicney and diminished antibody production, and one patient had antibody deficiency. IgG;. IgGj and IgM deficiency as well as growth hormone deficiency (lablc 1).

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were still presenting some immunoglobulins in the serum but not receiving immunoglobulins or immunomodulaling trealment except for patients 3 and 6 who were already receiving immunoglobulin substitution (Table I) . Both were receiving monthly do.ses of intramuscular injections of immunoglobulins. Their IgG K'A ratio is not shown as this reflects only the substitution. Patients 7 and 8 had IgG levels of 5.4 and 5.6 g.l respectively when serum uas sampled tor this study. However, hoth patients had antibody deficiency and their IgG concentration was deereasing. reaching the iowesl level in patient 7 of 2.2 g/l before treatment with immunoglobulins was started. Tbe serum samples of ali the patients had been obtained at different times and kept fro7en at 2(1 C" until measured. All patients had recurrent infections. Patient 4 also had autoimmune haemolytic anaemia and patient 5 developed severe juvenile rheumatoid arthritis. Patients 5 and 12 had protracted diarrhoea. Patient 6 had recurrenl herpes zoster infections, ehronic aggressive hepatitis, alopecia totalis as well as rheumatoid arthritis. Patienl y had agranulocytosis ( Table I) .

The concentrations of immunoglobulin G, A. and M were tneasured by FFISA [I I] and the total K/V, ratio was measured by nephelometry as described earlier [5] . The K:/. ratios for each of the serum polyclonal immunoglobulin classes G. A. and M were measured by using d solid-phase FLISA-sandwich method [ll|. AlTinity-purified goat antiserum directed againsl human gamma, alpha or mu heavy chains were used to capture IgG. IgA or IgM. respectively. Peroxidaselabelled goat anti-\ or anti-/. aniiserum was used as a second antibody. As standard serum, pooled serum from 500 healthy Dutch blood donors was used. As eontrol serum another batch of pooled serum from 500 healthy Dutch blood donors was measured al Ihree difTerent dilutions which were expected to he at dilferent points on the standard curve. The absorption was measured at 492 nm and the concentration ol'thc K and /. light chains was delermined from a standard curve.

The results of the IgG. IgA. and IgM K:/. ratio determinations were compared to a reference group [13] consisting of 134 healthy individuals. 114 children aged one month to 16 vears and 20 adult blood donors.

The KI/. light chain ratios deviated from our reference values in ten of the thirteen patients for oneor moreof the immunoglobulin classes or for the total K-:/. ratio (Fig. I) . Patients who developed CVID in early childhood (patients 1 5) tended to have more disturbed ratios than those presenting later in life (patients 6-8). For patients 3 and 6, IgG concentration and IgG K/A ratio is irrelevant as it refieets the immunoglobulin substitution whereas the IgM KJ?-ratio primarily concerns the patients" own immunoglobulin synthesis. Patient 12 who had protraeted diarrhoea had only a raised IgA K//. ratio with the other ratios within the normal range. Patient 13 with antibody deficiency syndrome and growth hortnone deficiency expressed increased K!/. ratios for all classes measured. Patient 1 had the lowest KJA ratios but did not differ clinically from the other patients with agammaglobulinaemia. Usually, in a given patient, the ratios were either all raised or all decreased.

All patients except patients 9 and 10 had a disturbed antibody response in vivo, measured as antibody titres against diphtheria, tetanus or poliomyelitis after immunization and/or as isoagglutinin titres (Table I) . Patienl 4 has not been immunized but his antibody response against various respiratory tract micro-organisms (adenovirus. coronavirus, influenza A and B. parainfluenzae I. 2 and 3. respiratory syneytial virus and mycoplasma) is absent. Peripheral blood lymphocyte stimulation by antigens In vitro was tested in twelve of the patients and was normal in all but one. Antigen synthesis after helix pommatia hacmocyanin vaccination was negative in eight out of the nine patients tested. The proliferative response of peripheral blood lymphocytes to PHA or PWM in vilro was normal, or only slightly disturbed, in all patients ( Table I) (Table I) . When tested. CD4' and CD8 ' eells were normal except for patienls 10 and 12 expressing rather low CD4' and CDS ' eells. respeetively.

Our findings indicate that in patienls with CVID or other humoral disturbances the production of the light chains as well as of the heavy chains is affected. In the four patients who developed CVID in childhood before puberty and did not receive immunoglobulin treatment, all Kl'/. ratios were abnormal, either increased or decreased. Only in the two patients with IgG;. IgG4, IgA and IgM deficiency, developing late onset agamaglobulinaemia after puberty, were all KJ?. ratios normal. Therefore, il can be suggested that the regulation of the light chains is affeeted in different ways, depending on the cause of the agammaglobulinaemia.

In an earlier study, an age-related increase of the total KU. ratio, and IgG and IgM KJ/. ratio was found whereas a decrease of the IgA h//. ratio was A. Haruldsson ct al. noled [13] . Apparently, in healthy children the regulation of ihe light chain synthesis is different for those various immunoglobulin classes. In pathological situations, however, abnormal wj'/. ratios were demonstrated for all serum immunoglobulins measured in several patients, indicating a more general defect in the light chatn regulation.

In patients 11,12 and 13 with antibody deficiency, the Kjk ratios were either normal or raised: decreased K!?. ratios were not found. One rnighl expect that the light chains play an important role in the antibody response. However, the primary response was impaired after irnmunization in ten of the eleven patients tested, independent of whether the patients had normal or abnormal ^•/A ratios. The response to a booster itnmunization was only positive in two sibs with agammaglobulinaemia wilh hyper IgM. Both expressed slrongiy increased IgM levels and a deereased IgM KO.. ratio. The isoagglutinin titre also an IgM antibody-was normal in these patients.

This was also demonstrated in patient 3 who had a slightly decrea.sed IgM KI/. ratio. This indicates thai despite a disturbed KJk ralio the antibody response may be normal. However, although the IgM KI/. ratio was decreased in these three patienls. they all expressed higheoncentrations of IgM K as well as IgM /. as their serum level of IgM was extraordinarily high. Whether normal anlibody levels can be produced wilh normal or decreased serum imtnunoglobuiin levels and abtiormal light chain ratios remains questionable.

We conclude that light chain production is affected in some humoral immunologieal disorders presenting with a disturbed heavy chain concentration. Furihertnore we conclude that both heavy and light chains can most probably be simultaneously but independently stimulated or inhibited in some immunological disorders. Disturbed light chains may contribute lo impaired antibody response in vivo or may possibly be a result of this abnormal response.

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Thymid-slimtilatltin auloantibodies usually contain only L-light chains: evidence Tor ihc "lorhidden clone" theory

Merogeneily of lySand 7Santi-g-globiilinsin rheumatoid arthritis and subacutc bacterial endocarditis

Bakkercn JAJM. Nephelomctry of the kappa.lambda light chain ratio in serum of normal and diseased children

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Bakkercn JAJM. Determination of kappa and lambda light chains in scrum immunoglobulinsG. A and M

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