Abnormal levels of the alpha chain of the CD22 adhesion molecule may account for low CD22 surface expression in chronic lymphocytic leukemia.
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Aged↗
Biomedical subjects
G Dumas
Publications and source records attributed to G Dumas.
[Dehiscence of the anterior semicircular canal and otosclerosis: a case report].
UNLABELLED: The dehiscence of the anterior semicircular canal is a new clinical entity, it is necessary to consider this when a gusher occurs during stapedial surgery. CASE REPORT: We report a rare case of dehiscence of the anterior canal associated with otosclerosis. This was revealed by a gusher during the initial stapedectomy. At 3 months, an obliteration of the dehiscence was necessary by middle cranial fossa approach (persistant vestibular symptoms), seven months later. Revision stapedial surgery resulted in complete closure of the air-bone-gap. CONCLUSION: High resolution CT scans of the temporal bone are the key to diagnosis. It is necessary to appreciate this pathology with advances in canal and vestibular surgery.
Early Diagnosis↗
[Ossiculoplasty with KURZ titanium prosthesis].
OBJECTIVES: Report the functional and anatomic results of ossicular reconstruction by titanium prosthesis. MATERIALS AND METHODS: Retrospective chart reviews were performed for 111 patients who had undergone titanium ossicular implants between November 1998 and 2002 (61 PORP, 50 TORP). The anatomical and audiometric data were analyzed on average at 3 and 20 months. RESULTS: At 20 months, the improvement of air-bone-gap mean was 12.7 dB with better results at low frequencies. The global success rate was 66% (PORP 77%, TORP 52%). It decreased significantly in the open techniques. Extrusion rate was low (2/111) and the labyrinthization rate was 3.6%. Twenty patients required a surgical revision (18%). In 9 patients, the prosthesis was too short. At long-term follow-up, the gains were stable in 60 patients, improved in 32 patients and worsened in 19 patients. CONCLUSION: The success rate is higher in the group of the PORP with the closed technique. The stability of the TORP in open technique still remains problematic. In all cases, the risk of extrusion requires a large cartilage graft recovering the plate of the prosthesis. The high rate of luxation (9/111 prosthesis too short) has led us to increase slightly the length of the prosthesis (+1.22 mm mean).
Adolescent↗
[Vestibular neurotomy versus chemical labyrinthectomy for disabling Menière disease].
OBJECTIVE: To evaluate the efficiency on the vertigos and the impact on the audition of the vestibular neurotomy (VN) and the chemical labyrinthectomy (CL) in patients with severe Menière's disease, in order to determine the precise place for each technique in treatment algorithm. METHOD: Retrospective study of 71 VN (performed between 1986 and 2003) and 35 CL (performed between 1997 and 2003). These two treatments both aim at obtaining a vestibular deafferentation in order to free definitely the patient of vertigo manifestations. Vestibular results have been assessed by caloric tests performed before and 6 months after treatment. Subjective success was evaluated by searching for recurrent attacks of vertigo and by the AAO-HNS (American Academy of Otolaryngology-Head and Neck Society) scale of subjective evaluation of vertigos (follow-up of 6.4 years after VN and 2.4 years after CL). Pure tone audiometry before treatment and then 6 months later was performed. Complications of two types of treatment were recorded and evaluated. RESULTS: In 90% of the cases after VN and 86% of the cases after CL, caloric tests indicated a strong vestibular hyporeflexy (hypovalence > 90%). Attacks of vertigo reoccurred in 5.6% of the cases when the hyporeflexy was strong and 85.7% of the cases when it was weak. The quality of the vestibular results on vertigo depends on the degree of hypovalence after treatment. An improvement of the AAO-HNS scale have been obtained in 93% of the cases in the NV group and in 81% of the cases in the LC group. Attacks of vertigo were recurrent in 7% of the patients operated on by VN and 11.4% of the patients treated by CL. Mean pure tone auditory thresholds changed from 50.24 dB HL to 55.64 dB HL (p=0.003) in the VN group and from 69.11 dB HL to 74.51 dB HL (p=0.41) in the CL group. Comparison of the variations of the mean pure tone auditory thresholds before treatment and 6 months after the end of the treatment doesn't show any significant difference between the 2 groups (p > 0.05). Impairment of the audition superior to 20 dB HL was observed in 8.5% of the patients of each group. The auditive results are similar in the 2 groups. CONCLUSION: These two methods of treatment can not be strictly compared due to several bias in this study. Indeed more patients were treated by VN with a longer follow-up and only the patients with a class C or D audition according to the criteria of the AAO-HNS could be treated by CL. The VN provides a better control of the vertigos than the CL which is an efficient method of treatment in invalidating Meniere's disease. In all the cases, the quality of the results on vertigos depends on the degree of hypovalence after treatment. The auditive results are similar. Since the results of the two treatments are similar, the simplicity of CL encourages us to broaden the indications and to modify the place of the VN in the therapeutic algorithm of Menière's disease.
Adult↗
[How to do a caloric test].
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Caloric Tests↗
[The outcome of treatments for carcinoma of the external auditory canal].
OBJECTIVE: A retrospective analysis of management and survival of patients treated for temporal bone carcinoma. PATIENTS AND METHODS: Thirty patients underwent treatment for carcinoma of the temporal bone. Twenty-five squamous cell carcinomas, 1 melanoma, 2 basocellular carcinomas and 2 adenoid cystic carcinomas were treated. Thirteen patients were treated before for the same disease. RESULTS: Staging revealed 12 T1 and T2, 6 T3 and 12 T4 tumours. The mean follow up was 5 years (2-276 months). The Kaplan Meier survival curves showed survival rates at 2 years of 82%, 67% and 32%, and at 5 years of 82%, 67% and 17%, respectively for the stages T1 or T2, T3 and T4. At the end of follow up at 9 years the survival rates were 66%, 66% and 17% for the stages T1 or T2, T3 and T4 respectively. Overall stages a complete remission was found in 65% and 23%, and deceased was 35% and 77%, respectively for the primary treatment group and the salvage surgery group. CONCLUSION: Long-term prognosis of the carcinoma of the external auditory canal mainly depends on the stage and primary treatment. Surgery (lateral temporal bone or subtotal temporal bone resection, both in combination with a neck dissection and a parotidectomy) and adjuvant radiotherapy is the treatment of choice for part of stage T1 and all T2 and T3 tumours. The improved survival (65%) of patients treated de novo compared with those treated with salvage surgery (23%) suggests that early referral and aggressive primary surgical treatment with postoperative radiotherapy offer the greatest chance of cure.
Adult↗
[Skull vibratory test in partial vestibular lesions--influence of the stimulus frequency on the nystagmus direction].
INTRODUCTION: Results of the skull vibratory test (SVT) in partial unilateral vestibular peripheral lesions (PUVL) are different from the results in total vestibular lesions (TUVL). AIM: To reveal a correlation between the results of the analysis of the skull vibratory nystagmus (SVN) horizontal component and the side of the lesion; to correlate these results with the stimulus frequency. To find out a predictive correlation between the SVN horizontal and vertical components and the topography of a vestibular lesion. To appreciate the degree of vestibular deafferentation (extended to high frequencies) provoked by gentamicin labyrinthectomy and its efficiency in Meniere's disease. PATIENTS AND METHODS: 53 patients with a SVN and a PUVL were included and compared with 10 TUVL and 10 normal subjects. Protocol included a HST (2 Hz), a SVT at 30, 60 and 100 Hz and a caloric test. Recordings were performed with a 2D and 3D VNG device. RESULTS: In PUVL, SVN at 30, 60 and 100 Hz was obtained in 80, 90 and 90% of cases respectively. SVN is correlated with the side of the lesion at 30, 60 and 100 Hz respectively in 65%, 63%, 80% of cases. SVN is not correlated with the side of the lesion in 20% of Meniere's disease, in 8% of vestibular neuritis and in 6% of vestibular schwannoma. In PUVL HSN is correlated with the side of the lesion in 69% of cases. The direction of the HSN and of the SVN was different in 23% when the nystagmus attended at the same time for both tests. In PUVL the direction of the SVN is different at 100 Hz and 30 Hz in 16% of cases when they are concomittant on the same patient. After Gentamicine labyrinthectomy, the coherence of the results in caloric test, HSN and SVN (areflexy and lesional nystagmus beating toward the safe side) was correlated with the efficiency of the therapy. A SVN vertical component was met in 10% of PUVL (essentially in anterior canal dehiscence and few cases of partial labyrinthitis). The horizontal SVN SPV is significantly slower in PUVL than in TUVL patients (p=0.0004). CONCLUSIONS: The SVT is a vestibular global and rapid test which explores high frequencies. In PUVL the direction of SVN is not always predictive of the side of the lesion and is sometimes depending on the stimulus frequency, the state of the vestibular lesion, the vestibular structure concerned (1/2 circular canals or otolithic organs) and the kind of sensory cells implicated in the lesion. In TUVL The direction of the SVN is always coherent with the side of the lesion (this is useful to predict the efficiency of a Gentamicine Labyrinthectomy). A SVN vertical component can mean a lesion of the vertical canal in PUVL.
Adolescent↗
[Vibratory test and head shaking test and caloric test: a series of 87 patients].
OBJECTIVES: The purpose of this work was to study the complementary contribution of the vibratory test (VT), the head shaking test (HST) and the caloric test (CT) in patients with total or partial vestibular lesions. We investigated the usefulness of these three tests, particularly the high frequency VT, for multiple-frequency vestibular study. MATERIALS AND METHODS: The study cohort included 40 patients with total vestibular lesions (TVL) and 47 patients with partial vestibular lesions (PVL), the latter group including 21 patients with recent Menière disease, 15 with sudden-onset loss of vestibular function (SLVF), 5 with tumors of the cerebropontine angle, and six with diverse conditions. The HST protocol was 2 Hz stimulation (head speed greater than 180 degrees /s). The VT used an ABC 100 Hz vibrator operating at 0.8 mm and an S stimulator delivering frequencies between 30 and 115 Hz during 10 s stimulations. An LIVN-2 videoscope (biodigital France) and a 2D and 3D videonystagmograph (synapsis France) were used for the recordings. Mastoid stimulation was used for the VT. RESULTS: For the 40 patients with TVL, the three tests (VT, CT, HST) were in agreement for all frequencies. The nystagmus produced by the VT demonstrated a horizontal component in 96% of the patients, a vertical component in 47%, and a rotational component in 30%. For the 47 patients with PVL, 9 of the 21 with Menière disease had a normal CT. Conversely, nystagmus was triggered by the HST in 10 and by the VT in 6. Nystagmus triggered by the VT and the HST was non-coherent with opposing direction in two-thirds of the patients. In certain cases, the VT demonstrated a variation in the direction of the nystagmus depending on the stimulation frequency, 30 or 100 Hz. Among the 15 patients with SLVF, the HST triggered nystagmus in only 5 and the VT in 14 (5 patients had nystagmus non-coherent with the side of the lesion). For the 5 patients with tumors of the cerebropontine angle (small neuroma or meningioma), the CT was negative in all 5, the HST was negative in 3, and the VT demonstrated lesional nystagmus in 4. Looking at the overall results, in the 47 patients with PVL (including 21 cases of Menière disease outside an acute phase) the CT demonstrated significant hypovalence in 70%, while the nystagmus demonstrated asymmetrical response in 44% when triggered by the HST and in 85% when triggered by the VT. CONCLUSION: The VT is less invasive than the HST, particularly for elderly patients with osteoarthritis. It would be interesting in patients with bilateral tympanic perforation since the CT cannot be performed. It can reveal vestibular asymmetry. For unilateral partial vestibular lesions, the VT triggers nystagmus more often than the HST. It is particularly sensitive between acute episodes in patients with Menière disease. A discordance between the direction of the nystagmus triggered by the HST and the VT is particularly frequent in patients with labyrinthine hydropsis who exibit a normal CT. In certain cases of apparent bilateral areflexia to the CT for low frequencies, the VT can disclose vestibular asymmetry for high frequencies. The nystagmus triggered by the VT begins and ends with stimulation with little or no tiring. The nystagmus triggered by the HST occurs after the stimulation and depends on the frequency of the head shaking. Thus, the HST (2 Hz and its harmonics), the VT (100 Hz) and the CT (<0.01 Hz) all make significant contributions to multiple-frequency analysis of vestibular function, particularly useful in patients with partial vestibular lesions. These tests probably solicit cells with different topographies or different frequency sensitivities.
Aged↗
[Cavernous haemangiomas: hearing and vestibular inaugural symptoms].
INTRODUCTION: Cavernous haemangiomas (cavernomas)(CH) are relatively rare (2% of cranial tumoral pathology) vascular malformations mostly observed in the central nervous system. Their most common topographical site in brain stem is midline in the pons, for which clinical course may mimic symptoms of peripheral origin (sudden deafness, fluctuating hearing loss, Meniere-like vertigo). AIM: To establish the correlation between the clinical manifestations of hearing and balance disturbance and the anatomical site within the pons of cavernous haemangiomas, and to describe their clinical features, and the findings on auditory brainstem response (ABR) and magnetic resonance imaging (MRI). To propose a literature review about CH and its implications. MATERIAL AND METHOD: We made a retrospective review of the histories of three patients aged 24, 44 and 45 years, diagnosed as having cavernomas of the brainstem in which audiometric evaluation, videonystagmography (VNG), ABR and imaging techniques lead to the diagnosis of intracranial cavernoma. RESULTS: The clinical and radiological files were reviewed and a direct relationship between symptoms and localization was found in all 3 patients, especially in relation to our understanding of the auditory and vestibular pathways within the brainstem. CONCLUSION: The literature regarding cavernomas of the pons is reviewed and the clinical, neuroimage, pathological, natural course and management aspects of the disease are discussed. We recommend the use of cerebral MRI for initial diagnosis which shows a typical rosette-like appearance with a heterogeneous signal on T2-weighted images, along with follow-up and investigation into similar profiles among family members. At present there is no consensus about the treatment to follow when cavernomas are located in the brain stem. There is no specific medical treatment for this condition, and surgery is indicated only exceptionally. Anticoagulant therapy, platelet-dispersing medication and violent sports activities are contraindicated.
Adult↗
Retention and defective assembly of the B-cell receptor in the endoplasmic reticulum of chronic lymphocytic leukaemia B cells cannot be reverted upon CD40 ligand stimulation.
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Antigens, CD↗
Vitrification of cryoelectron microscopy specimens revealed by high-speed photographic imaging.
Cryoelectron microsopy is a widely used technique to observe biological material in an almost physiological, fully hydrated state. The sample is prepared for electron microsopy observation by quickly reducing its temperature to -180 degrees C. The high-speed cooling induces the formation of vitreous water, which preserves the sample conformation. However, the way vitrification occurs is still poorly understood. In order to better understand the phenomenon, we have used a stroboscopic device to visualize the interaction between the electron microscopy grid and the cryogen. By blocking the free fall of the plunger once the grid has penetrated the coolant by half its diameter, we have elucidated the way in which vitrification propagates. The findings were confirmed by numerical simulation. In addition, according to our observations, we now present an alternative way to prepare vitreous specimens. This new method, with the grid parallel to the liquid cryogen surface, decreases evaporation from the sample during its free fall towards the coolant and at the same time achieves a more uniform vitrification over the entire surface of the specimen.
Cryoelectron Microscopy↗
[Nystagmus and vibration test research of mechanisms, theoretical methods: on 52 cases of unilateral vestibular lesions].
OBJECTIVE: The aim of the present study was to examine the characteristics of the Vibratory Nystagmus (VN) optimise the topography and the frequency of the stimulus, determine the origin of the VN and analyse its clinical implications. MATERIAL AND METHOD: 52 severe unilateral vestibular lesions (SUVL) (post-surgical vestibular areflexy) were studied. The vibratory nystagmus was measured by 2D and 3D videonystagmography (Synapsis, France). The stimulus was applied with a 3S vibrator at the vertex, both mastoïds, and posterior cervical muscles at frequencies ranging from 20 to 150 Hz. For topographic optimisation, stimulation was given with S vibrator (Synapsis, France) at 100 Hz. The interferences between the vibratory test (VT) and the caloric test (CT) were studied on the normal ear (in 11 subjects). The same study was carried with the optokinetic test. RESULTS: The VT revealed a defective nystagmus at all frequencies of stimulation. Optimal response was obtained in a band frequency of 80-120 Hz. Stimulations at 100 Hz showed optimal responses for mastoïd topography (responses in 96% of the cases). Stimulation at the posterior cervical muscles and at the vertex indicated respectively a response in 90% and 60% of the cases. The efficiency of the mastoïd stimulation is not correlated with the side of stimulation (p = 0.9). The interference between the VT and caloric test (CT) at cold water (30 degrees et 20 degrees C) exhibited the inversion of the caloric nystagmus during the vibrator stimulation. The resulting nystagmus is respectively an algebric subtraction or addition between the pre-existing caloric nystagmus and the value of the vibratory nystagmus obtained before caloric test. Adaptation of the VN is moderate. The interference between the VT and the optokinetic test resulted in a subtraction or addition effect, according to the side of the lesion and the direction of the optokinetic stimulus. CONCLUSION: The VT is an efficient stimulation in mastoïd topography. The vestibular contribution is bilateral by bony conduction of the vibration, it explores frequencies ranging from 30 to 120 Hz, with a maximum of response at 100 Hz. The VT interacts with the caloric test and the optokinetic test. The stimulation is very strong, and is able to inverse the caloric nystagmus at cold water stimulation (20 degrees C). In labyrinthine-defective subjects, the VN is always defective at all frequencies, whatever is the topographic location of the stimulus, and the position of the head.
Caloric Tests↗
[Nystagmus and vibratory test: evidence for mechanism. Material conditions and methods in the fast detection of unilateral vestibular lesions].
OBJECTIVE: The aim of the present study was to examine the characteristics of vibratory nystagmus (VN), optimise the topography and the frequency of the stimulus, determine the origin of the VN and analyze its clinical implications. MATERIAL AND METHOD: Fifty-two severe unilateral vestibular lesions (SUVL) (post-surgical vestibular areflexy) were studied. The vibratory nystagmus was measured by 2D and 3D videonystagmography (Synapsis, France). The stimulus was applied with a 3S vibrator at the vertex, both mastoïds, and posterior cervical muscles, at frequencies ranging from 20 to 150 Hz. For topographic optimization, stimulation was given with S vibrator (Synapsis, France) at 100 Hz. The interferences between the vibratory test (VT) and the caloric test (CT) were studied on the normal ear (in 11 subjects). The same study was carried out with the optokinetic test. RESULTS: The VT revealed a defective nystagmus at all frequencies of stimulation. Optimal response was obtained in a band frequency of 80-120 Hz. Stimulations at 100 Hz showed optimal responses for mastoid topography (responses in 96% of the cases). Stimulation at the posterior cervical muscles and at the vertex indicated respectively a response in 90% and 60% of the cases. The efficiency of the mastoid stimulation was not correlated with the side of stimulation (p=0.9). The interference between the VT and caloric test (CT) with cold water (30 degrees C and 20 degrees C) exhibited the inversion of the caloric nystagmus during the vibrator stimulation. The resulting nystagmus was respectively an algebraic subtraction or addition between the pre-existing caloric nystagmus and the value of the vibratory nystagmus obtained before the caloric test. Adaptation of the VN was moderate. The interference between the VT and the optokinetic test resulted in a subtraction or addition effect, according to the side of the lesion and the direction of the optokinetic stimulus. CONCLUSION: The VT is an efficient stimulation in mastoid topography. The vestibular contribution is bilateral by bony conduction of the vibration, it explores frequencies ranging from 30 to 120 Hz, with a maximum of response at 100 Hz. The VT interacts with the caloric test and the optokinetic test. The stimulation is very strong, and is able to inverse the caloric nystagmus at cold water stimulation (20 degrees C) In labyrinthine-defective subjects, the VN is always defective at all frequencies, whatever the topographic location of the stimulus, and the position of the head.
Follow-Up Studies↗
Do CLL B cells correspond to naive or memory B-lymphocytes? Evidence for an active Ig switch unrelated to phenotype expression and Ig mutational pattern in B-CLL cells.
Recent work suggests that chronic lymphocytic leukemia (B-CLL) expressing unmutated immunoglobulin V genes could correspond to the proliferation of naive B cells whereas those expressing mutated genes, may correspond to the proliferation of post-germinal center B cells. Current data from gene profiling expression have failed to demonstrate a clear-cut distinction between these two forms of B-CLL disease. In the present study, we have investigated the complete V(H) nucleotide sequence and the presence of RNA transcripts from different C(H) domains in 25 B-CLL patients. Our results demonstrate that: (1) expression of IgD is not related to the mutational frequency and activation of the isotype switch pathway; (2) isotype switch, leading to simultaneous expression at the transcriptional and protein level of IgM, IgD, IgG and IgA, occurs in a small percentage of patients, and (3) different mechanisms such as VDJ duplication and trans-splicing or RNA splicing of long nuclear transcript, could be involved in isotype switch. Our results highlight the difficulty in assigning a normal counterpart to B-CLL cells and raise the possibility that a different B cell development pathway, independent from classical germinal centers, might exist in B-CLL.
Adult↗
[Cavernous angiomas of the brain stem: auditory and vestibular manifestations].
AIMS: To establish the correlation between the clinical manifestations of hearing and balance disturbance and the anatomical site within the pons of cavernous angiomas, and to describe their clinical features, and the findings on ABR and MRI. MATERIALS AND METHODS: Two clinical cases of cavernous angioma with cochlear and vestibular manifestations underwent audiometric evaluation, with VNG and ABR as well as CT and MRI scans. CONCLUSION: Cavernous angiomas are rare (less than 2% of intra-cranial space-occupying lesions). Their most common topographical site is midline in the pons, and may give rise to symptoms in attacks (due to episodes of bleeding within the tumour) which may mimic symptoms of peripheral origin (sudden deafness, fluctuating hearing loss, Menière-like vertigo). There may be ectopic remnants of the embryonic blood vascular system. They may be associated with other malformations (intra-cerebral venous angiomas, cavernous angiomas at other sites). Their development is often by sudden progression which may be dramatic, and have accompanying neurological features. For investigating the hearing and balance, ABR is an excellent test, giving a typical picture of a retro-cochlear lesion that necessitates progression to MRI, the investigation of choice. This will demonstrate the typical rosette-like appearance with a heterogeneous T2 image (a less dense peripheral ring, with a denser central signal). There is no specific medical treatment for this condition, and surgery is indicated only exceptionally. There is a contraindication to anticoagulant therapy, to platelet-dispersing medication and to violent sports activities. Two cases of cavernous angioma are reported; one was more anteriorly situated, and had mainly vestibular features, and the other was more posterior near the floor of the IVth ventricule, with mainly auditory features. The correlation of the anatomical and clinical findings with those of the MRI are discussed, especially in relation to our understanding of the auditory and vestibular pathways within the brainstem (the auditory striae, the crossed auditory pathways and the nuclei of the corpus trapezoideum for the auditory effects, and the paramedian reticular nucleus and crossed inter-commissure pathways to the cerebellum and vestibular nuclei, together with the proximity of the direct midline vestibulo-spinal tract, for the vestibular effects).
Adult↗
Diagnostic value of vibration-induced nystagmus obtained by combined vibratory stimulation applied to the neck muscles and skull of 300 vertiginous patients.
On subjects with unilateral vestibular dysfunction, the application of a vibratory stimulation (100 Hz) to the two mastoids and the vertex, and to the right and left dorsal neck muscles produces a nystagmus directed towards the good ear in 85% of patients. Fixation must be suppressed by Frenzel's glasses or video nystagmoscopy. To be significant this nystagmus must appear in at least 3 of the 5 vibratory stimulated sites. On healthy subjects nystagmus is present in 6% of cases but never in those below 30 years. In subjects affected by central vertigo, nystagmus was elicited in 10% of cases and in subjects suffering from vertigo of unknown origin in 6% of cases. Vibration nystagmus which stops immediately after stimulation differs from head shaking nystagmus which is present in only 34% of unilateral vestibular dysfunctions. Vibration occasionally produces a pseudo-caloric nystagmus which persists after stimulation. We believe that vibratory stimulation is a useful test, quick and easy to perform. In conjunction with questionnaires, clinical examination, positional testing and the results of audiometry, it gives an immediate indication of a peripheral lesion when the vertigo is seen for the first time. With unilateral deafness, a positive test leads one to suspect an acoustic neuroma. Conversely if the test becomes negative after a vestibular neuritis when it was initially positive, it is a sign of recovery.
Adolescent↗
Negative regulation of autoreactive B cells in transgenic mice expressing a human pathogenic cold agglutinin.
Cold agglutinins (CA) are autoantibodies that bind to erythrocyte carbohydrates at low temperatures and induce complement-mediated cell lysis, thus causing hemolytic anemia. Tolerance mechanisms towards CA-expressing B cells and the factors inducing pathogenic CA production are unknown. In order to develop an animal model for CA disease, we have produced transgenic mice expressing the heavy or the light chain of a human CA, previously shown to be pathogenic to the mouse. Expression of the human H chain alone resulted in a B cell maturation block at the pro-B stage, and did not induce allelic exclusion. In double-transgenic mice, co-expression of the human H and L chains restored B cell development but the majority of bone marrow cells expressing the human IgM were eliminated by deletion. In the periphery, B cells were depleted, and a large proportion of the remaining cells co-expressed a human and a murine H chain, secreting "mixed" IgM. A few autoreactive cells, predominating in the peritoneal cavity, escaped tolerance mechanisms and secreted transgenic IgM. The autoreactive B cells are amenable to polyclonal stimulation, making these transgenic mice a suitable model for a human autoimmune disease.
Agglutinins↗
Can isotype switch modulate antigen-binding affinity and influence clonal selection?
Four different monoclonal Ig (MIg) (IgA1kappa, IgG1kappa, IgG2kappa and IgG4kappa) displaying anti-tubulin activity were detected in the serum from a lymphoma patient. The complete sequence of three of these MIg showed identical V(H) and V(L) domains and the presence of mutations compatible with an antigen-driven process. Surprisingly, despite complete homology in their variable domains, IgA1kappa, IgG1kappa, or their Fab fragments bound to a common motif recognized in beta tubulin, with significant differences in affinity (IgA1kappa 1.52x10(-8) M, and IgG1kappa 2.09x10(-7) M). To substantiate these results, the V(H) and V(L) domains from IgA1kappa were cloned and introduced into expression vectors containing the constant kappa exon and either the mu or the gamma1 constant exon, and complete recombinant IgMkappa and IgG1kappa were obtained. Like the IgA1kappa, the IgMkappa construction bound to the tubulin epitope with consistent affinity (7.7x10(-9) M), whereas the IgG1kappa construction displayed a significantly lower affinity (3.28x10(-7) M). These results provide definitive evidence that isotype can influence binding affinity to antigen and suggest that malignant transformation occurred at the germinal center once the mutational process was achieved and the switch process was still active.
Amino Acid Sequence↗