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July2005 Vol.42 Issue:      2 Table of Contents
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Light Chain Immunoglobulins in Patients with Systemic Lupus Erythematosus and Central Nervous System Involvement

Adel S. Abdel-Ghaffar1, Magdy A. Aidaros1, Mohamed G. Aodalla2

Departments of Neurology1, Bacteriology2, Zagazig University



ABSTRACT

This study was done on 15 patients with systemic lupus erythematosus ( SLE) and central nervous system (CNS) involvement (CNS – SLE) (group 1), Eight patients with SLE without CNS involvement (group II) and 10 normal control subjects (group III). Clinical assessment, radiological and routine laboratory investigation were done, in addition to determination of light chain immunoglobulin kappa (k) and lambda (L) before and after treatment. There was statistical significant elevation of both Igk and IgL indices in group I compared to group II and group III ( P <0.05) and both indices correlated well with each other in group I. There was statistical significant decrease of both Ig k and IgL indices when the CNS manifestation subsided after medical treatment in group III. These observation suggestive that serum free light chain immunoglobulins measurements will be of considerable benefit for diagnosis and disease management.

(Egypt J. Neurol. Psychiat. Neurosurg., 2005, 42(2): 273-278).

 




INTRODUCTION

 

Systemic lupus erythematosus (SLE) is an inflammatory, multisystem disorder with arthralgia and rashes as the most common clinical features, and cerebral  and renal disease as the most serious problems. Central nervous system (CNS) involvement in (SLE) is a relatively common and serious complication of the disease1. The prevalence of clinical neuropsychiatric SLE vary from 14% to 75% reflecting variable diagnostic methodologies and criteria2. Neuropsychiatric SLE includes cerebrovascular events, seizures, neuropathy, headache, movement disorders, Cerebellar ataxia, cranial nerve lesions, aseptic meningitis, transverse myelitis, psychosis and organic brain syndrome3.

However, useful markers for systemic disease activities in SLE, such as total   hemolytic complement, Westergren erythrocyte sedimentation rate (ESR) and anti DNA antibody titer are often useless to evaluate CNS disease activity. Many studies reported that the serum from patients with SLE and CNS involvement (CNS – SLE) contained neuron reactive antibodies. They attributed the pathogenesis of CNS – SLE to the antibodies. Several abnormalities of immunoglobulins in CNS – SLE have been described including the elevation of its IgM, IgG and IgA. The recently discovered role for Ig free light chains in mediating hypersensitivity – like responses sheds new light on their potential role in immune responses4. Free light chains are homogeneous populations of kappa (K) or lambda (L) immunoglobulin light chain molecules produced by malignant clones of B- cells. They are important markers for identifying and monitoring SLE patient with CNS activity5.

The aim of this work is to study light chain immunoglobulins kappa and lambda in a group of SLE patients with central nervous system involvement and correlate this with clinical course.

PATIENTS AND METHODS

 

Twenty three patients with SLE, who previously or currently satisfied the 1982 revised criteria for the classification of SLE6. These patients were classified into two groups:

Group I : fifteen of the 23 patients had symptoms or signs of CNS involvement. such as seizure, personality disorders, headache, stroke (thrombosis), or focal signs without any predisposing conditions (e.g. arteriosclerosis, hypertension, and uremia), were diagnosed as CNS – SLE. These patients consisted of 4 males and 11 females, aged 15-56 years (33.0±12.9, mean±SD) serum specimens were obtained from each patient, usually within one week from the onset of CNS involvement. These patients were reevaluated clinically when their symptoms improved usually in 2 months after successful treatment in form of moderate to high dose of corticosteroids (30-80 mg/day) with good suppression of diseases manifestation which another specimens were obtained.

 Group II: Eight of the 23 patients with active SLE without CNS involvement . they consisted of 8 female aged 26-51 years (41.0±9.8, mean±SD). The duration of lupus disease was 1-6 years with a mean of (3±1.8).

Group III: Included 10 normal subjects. 6 females and 4 males, aged 18-36 years  (27.4±5.9, mean±SD).

 

All subjects were submitted to the following :

-       Full history taking and clinical examination.

-           MRI of the brain. Electroencephalography and psychometry.

-           ECG and echo cardiography were done for evaluation of any source of embolization.

-           CBC, urine analysis, blood urea, serum creatinine and blood sugar level.

 

-                      Assay of :

.     Serum antinuclear antibodies (ANA)

.     Serum anti DNA by (ELISA) .Double-stranded DNA finding is specific for SLE (N<100 IU/ml)

-           Serum IgM, IgG and IgA  were measured by single radial immunodiffusion assay and using endoplates contain a buffered agarose antiserum at PH 7.2 7.

-           Principle of the determination of serum kappa and lambda is based on the reaction between kappa or lambda as antigen and the specific antiserum as antibodies. This reaction form an insoluble complex producing turbidity which is measured spectrometrically at 340 nm 8.

-           Blood samples were collected from patients and control groups. Sera were separated and kept frozen at –20c till the time of determination of the immunoglobulins.

 

RESULTS

 

In our study, we have observed that IgK index and IgL index were significantly elevated in CNS- SLE patients compared with SLE patients without CNS involvement or with control groups table (1, 2). Both Ig-k and Ig-L indices correlated significantly with each other in CNS –SLE patients compared with other two groups (Table 3). In SLE patients without CNS involvement neither Ig-k or Ig-L indices was significantly elevated compared with the control group (Table 4). Both Ig-k and Ig-L indices were remarkably decreased in each patient of group I when the CNS symptoms subsided after treatment indicating that the elevation of the indices were not attributable to SLE itself (Table 5), furthermore the elevation of IgM, IgA and IgG indices have been reported compared to group II (Table 6).


Table 1. Comparison of light chain immunoglobulin between patients of group I and group III.

 

 

Group I

Group IIII

t

P

Mean±SD

Mean±SD

Kappa

Lambda

288.4±80.9

153.7±46.2

145.3±35.1

75.6±26.7

5.2

4.81

<0.001 H.S

<0.001 H.S

 

Table 2. Comparison of light chain immunoglobulin between patients of group I and group II.

 

 

Group I

Group II

t

P

Mean±SD

Mean±SD

Kappa

Lambda

288.4±80.9

153.7±46.2

172.4±42.5

98.0±36.6

5.3

4.59

< 0.001 H.S

< 0.001 H.S

 

Table 3. Correlation between kappa and Lambda.

                         

 

r

P

Sig.

Kappa & Lambda

0.44

<0.01

H.S.

 

Table 4. Comparison of light chain immunoglobulin between patients of group II and group III.

 

                 

 

Group II

Group III

t

p

Mean±SD

Mean±SD

Kappa

Lambda

172.4±42.5

98±36.6

145.3±35.1

75.6±26.7

0.87

1.63

0.6 NS

0.11 NS

                   

 Table 5. Changes of light chain immunoglobulin in patients of group I before and after treatment.

              

 

Before treatment

After treatment

Paired t

P

Mean±SD

Mean±SD

Kappa

Lambda

288.4±80.4

153.7±46.3

160.8±50.4

103.4±19.5

7.96

3.28

<0.001H.S

<0.001H.S

 

 

Table 6. Comparison of immunoglobulin between patients of group I and group II.

 

 

Group I

Group II

t

P

Mean±SD

Mean±SD

IgM

IgG

IgA

121.1±37.2

1404±290.0

258.4±83.8

98.6±24.2

1403±233.8

224.5±59.1

2.156

0.006

2.759

<0.05

0.99

<0.05

 

  Table 7. Neurological finding in patients of group I.

 

 

Case No

Stroke (thrombosis)

Seizures

Migraine headache

Peripheral neuropathy

Personality disorder

1

+ve

-ve

-ve

 

 

2

-ve

-ve

+ve

+ve

-ve

3

-ve

+ve

-ve

-ve

+ve

4

+ve

-ve

-ve

-ve

+ve

5

+ve

-ve

-ve

-ve

-ve

6

+ve

-ve

-ve

-ve

+ve

7

-ve

+ve

-ve

+ve

-ve

8

-ve

-ve

-ve

+ve

-ve

9

-ve

-ve

-ve

-ve

+ve

10

+ve

+ve

-ve

-ve

-ve

11

+ve

-ve

+ve

-ve

+ve

12

-ve

+ve

+ve

+ve

+ve

13

+ve

-ve

-ve

-ve

-ve

14

-ve

+ve

-ve

+ve

+ve

15

+ve

-ve

-ve

-ve

-ve

 

 

 

 

DISCUSSION

 

This finding is in agreement with many studies which they found that both of the Ig-K and Ig-L indices were significantly elevated, indicating the increased immunoglobulines synthesis of both kappa and lambda types, in patients with CNS- SLE. Moreover, the Ig-k and Ig-L indices correlated with each other, and both indices were found to decrease remarkably when the CNS manifestation subsided after successful treatment.

Immunoglobulin subunits are formed by the jointing of two heterodimers, comprising a light (L) - chain and a heavy (H) chain, by disulphide bridges. Both H- chains and L- chains have a role in antigen recognition but solely  the H- chains determine the effector functions of different Ig subclasses. In the mammalian immune system. Two Isotypes of IgL- chains are used K and L. It has been long recognized that B-cells not only produce and secrete Igs formed from these subunits but also secrete a substantial amount of K and L free L- chain into serum11. Besides their antigen- binding capability, different properties have been described for Ig free L – chains including specific protease activity and the ability to activate the alternative complement system. Recently, they have demonstrated that Ig free L- chains can elicit mast cell mediated hypersensitivity responses and have a crucial role in the immunomechanism of contact sensitivity responses13.

The pathogenesis of CNS involvement in SLE remain unclear but many studies have observed the elevation of IgM, IgA and IgG index, and intrathecal synthesis of both Ig-k and Ig-L was elevated in patient with CNS –SLE. Also they have observed, that high antineuronal antibody levels. They proposed two possibilities as the mechanisms for that abnormality. One is that antineural antibodies from the systemic circulation might have been concentrated. Within CNS, and the other is that the antibodies might have been produced locally within CNS. These observations suggest that antineural antibodies may be produced as a result of polyclonal B-lymphocyte activation within CNS9.

We concluded that the high levels of light chain immunoglobulin K and L may play an important role for CNS involvement in SLE patients. Screening of those patients for K and L immunoglobulin is therefore of diagnostic and prognostic value.

 

REFERENCES

 

1.      Bernstein RM: Cerebral lupus: J. Rheumatol: 1982: 9: 817-818.

2.      Carbotte S.M., Denburg S.B., Denburg J.A.: Prevalence of cognitive impairment in SLE J. Nerve Ment. Dis. 1986, 174: 357-64.

3.      Mc cune W.I. and Globus J. Neuropsychiatric lupus Rheum Dis. Clin. North. Amer. 1988, 14: 149-67.

4.      Frank A. Redegeld and frans P.: Immunoglobulin free light chains and mast cells: Trends in Immunology: 2003, 24(4): 181-185.

5.      Bradwell A., Carr-smith HI, And Mead G.: Serum free light chain immunoassays and their clinical application: clinical and applied immunology Reviews: 2002, 3: 17-33.

6.      Tan EM, Cohen AS. Fries JF. et al: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum: 1982, 25: 1271-1277.

7.      Protein reference unit hand book of clinical Immuno chemistry. 1986.

8.      Mancine G., catbonara A., and Herenu J. :Immunochemical quantitation of antigen by   Single radial immunodifussion. Immunochemistry 1965, V.2, 235-254.

9.      Shunsei H- and terumasa M., : increased immunoglobulin synthesis of both kappa and lambda types in patients with systemic lupus Erythematosus and central nervous system involvement. J. of Rheumatology: 1986, 22: 715-721.

10.    Lamers K.D: Free k light chains versus IgG finding in neurological disorder. J. Neuroimmunol. 1995, 62: 19-25.

11.    Bradwell A.R.: Highly sensitive, automated immuno assay for immunoglobulin free light chain in serum. Clin. Chem.:2001, 47: 673-680.

12.    Takanari N, and Atsuo N., : ELISA for free light chains of human immunoglobulines using monoclonal antibodies. J of immunological Methods: 2003, 275: 9-17.

13.    Redegeld F. A.: immunoglobulin free light chain elicit immediate hypersensitivity like response Nat . Med.: 2002, 8: 694-701.


 


الملخــص العــربى

 

المفاهيم المناعية فى مرضى الذئبة الإحمرارية وعلاقته بالإصابات العصبية

 

أجريت هذه الدراسة على ثلاثة وعشرون مريضاً يعانون من مرض الذئبة الإحمرارية  وقد تم تقسيمهم إلى مجموعتين:

1-     المجموعة الأولى: وتشتمل على خمسة عشر مريضاً بالذئبة الإحمرارية مصحوباً بأعراض إصابة الجهاز العصبى المركزى.

2-     المجموعة الثانية: وتشتمل على ثمانية مرضى بالذئبة الإحمرارية ولا توجد أعراض عصبية.

3-  المجموعة الثالثة: وتشتمل على عشرة أشخاص طبيعية لمجموعة ضابطة وقد تم فحص المرضى إكلينيكيا وتقيمهم عصبيا, إجراء تصوير رنين مغناطيسى للدماغ, الفحوصات المعملية الروتينية بالإضافة إلى تقييم للسلسلة الخفيفة للأجسام المناعية ( كابا – لامدا) قبل العلاج وبعد شهرين من تعاطى عقار الكورتيزون.

ولقد وجدت علاقة ذات دلالة بين ارتفاع مستوى كلاً من كابا ولامدا بمرضى المجموعة الأولى بالمقارنة بالمجموعة الثانية والأولى. وأن هذا الارتفاع فى مستوى كلاً من كابا ولامدا كان متناسبا مع بعضهما. وأيضا علاقة إحصائية ذات دلالة بين انخفاض مستوى كلاً من كابا ولامدا مع تحسن الأعراض العصبية بعد العلاج.

وجدت علاقة إحصائية ذات دلالة بين كابا ولامدا  قبل وبعد العلاج وأيضا بالنسبة للمجموعة المقارنة. وبذلك يمكن استخدام السلسلة الخفيفة للأجسام المناعية فى تشخيص ومتابعة هؤلاء المرضى.



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