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Resolution of PANDAS Like Symptoms by IVIG in a Patient with Specific Antibody Deficiency against Polysaccharide Antigens
Resolution of PANDAS Like Symptoms by IVIG in a Patient with Specific Antibody Deficiency against Polysaccharide Antigens A. L. B. Hersh, L. Geng, A. Cushing-Ruby, H. Jyonouchi; Allergy and Immunology, UMDNJ, Newark, NJ. RATIONALE: PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) is a clinical entity with diagnostic criteria of prepubertal onset of symptoms, sudden onset or episodic course of symptoms, and temporal association of neuropsychiatric symptoms (tics, OCD, anxiety) with Group B Streptococcal infection. The pathogenesis of PANDAS remains controversial. We present a case of specific antibody deficiency to Str. Pneumoniae, with IgG2/IgG4 deficiency, whose clinical features include PANDAS like symptoms temporally associated with sinopulmonary infections. CASE HISTORY: 10 yo male developed neuropsychiatric symptoms (facial tic, psychogenic cough) after having Pneumonia in January, 2002, and was suspected of having PANDAS based on his clinical features and elevated ASO/anti-DNAse B Antibody titers in 2003. Despite antibiosis (Azithromycin and Amoxicillin-Clavulanate), the patient had recurrent sinopulmonary infections that correlated to the frequency and severity of behavioral symptoms. RESULTS: Conventional immune workup revealed low IgG2/IgG4 levels, suboptimal response to Pneumovax, and rapid decline of Pneumococcal Antibody titers. His peripheral blood mononuclear cells and peripheral blood derived macrophages produced low levels of proinflammatory cytokines (TNF-, IL-6, IL1-, and IL-12p40) in response to lipopolysaccharide, without TLR4 polymorphisms (Asp299Gly and Thr399lle). IVIG (0.6 g/kg/dose q3weeks) was started and there was nearly complete resolution of sinopulmonary infections and PANDAS like symptoms. Behavioral symptoms often reappear two to five days prior to next IVIG infusion. CONCLUSIONS: PANDAS symptoms may not be solely associated with Streptococcal infections, but could be related to other microbial infection in the presence of dysregulated inflammatory/immune responses and, in such conditions, IVIG may reveal superior therapeutic effects over antibiosis.
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ABR and DPOAE in Tubulin Based Induced Autoimmune Hearing Loss M. Habiby Kermany, B. Zhou, M. Yoon, T. Yoo; Allery/Immunology, University of Tennessee, Memphis, TN. RATIONALE: Auditory brainstem responses (ABR) is used for detecting electrical signals of neural transmissions from the inner ear hair cells to central auditory nuclei in the brain, while distortion product of otoacoustic emission (DPOAE) is used for testing functional status of the cochlear hair cells. DPOAE tests the function of cochlear structures. The combination of ABR and DPOAE provide detailed information on physiological defects in auditory pathway. Previous studies show that tubulin is a major constituent protein of microtubules, which are prominent structures in the sensory and supporting cells of the inner ear and is an autoantigen to the inner ear. METHODS: In current study, Balb/C mice presented autoimmune sensory neural hearing loss after immunization with high dose purified tubulin. Six weeks after the second booster, the sensorineural hearing loss was determined by elevation of ABR threshold in alternative polarity clicks and three different frequency levels: low (8KHz) middle (16KHz) and high (32KHz). RESULTS: ABR pick amplitude reductions show significant (P<0.05 mice# 28) as well as significant pick latencies. DPOAE also show significant elevation of threshold in low (8KHz) middle (16KHz) and high (32KHz) frequencies respectively (P<0.05 mice# 28). Degenerated spiral ganglion and cochlear hair cells were found in the inner ears under light microscopic assay. CONCLUSIONS: These results support studies which demonstrate that tubulin induces experimental autoimmune hearing loss in mice and the conclusion that tubulin is an autoantigen to inner ear. Electrophysiology
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data also reveals that this autoimmune damage affects the entire cochlea, from apical to basal turn (Low ~ High frequencies). Functional Regulation of Normal and SLE Plasma Cells by DCC (Deleted in Colon Cancer) and its Ligand Netrin-1 P. L. Lugar1, R. Slota1, R. T. Fischer1, D. Withers1, P. Pisitkun1, P. E. Lipsky2, A. C. Grammer1; 1Niams, dhhs, NIH, Bethesda, MD, 2Niams, dhhs, Autoimmunity Branch, NIH, Bethesda, MD. RATIONALE: Human B cell populations were examined for the expression of Netrin-1 and DCC, a gene that resides in the 18q12-q21 SLE (Sytemic Lupus Erythematosus) susceptibility locus and has been linked to several autoimmune diseases including SLE. Netrin-1 is a soluble ligand for DCC and has been reported to be a chemoattractant for DCCexpressing cells. METHODS: To examine the potential role of DCC and Netrin-1 in normal and autoimmune human B cell function, quantitative PCR, microarray, multiparameter flow cytometry and immunohistology were used to examine differential expression and gene targets of the Netrin1- DCC interaction. RESULTS: Both DCC and Netrin-1 were highly expressed by plasma cells from tonsil and SLE peripheral blood. By immunohistological analysis of tonsillar tissue, DCC antibody identifies plasma cells with a typical clockwork pattern in situ. Stimulation of highly purified tonsillar with Netrin-1 induces changes in cytokine receptors, chemokine receptors and immunoglobulin itself. CONCLUSIONS: Together, these results indicate that Netrin-1 interacts directly with DCC expressed on plasma cells to regulate differentiation and function. Dysregulation of DCC function may play a role in the pathogenicity of diseases that are mediated by abnormal plasma cell function such as SLE.
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Infliximab Related Lupus and Associated Valvulitis
T. Chadha, J. E. Hernandez; Baylor College of Medicine, Houston, TX. RATIONALE: Anti-TNF agents have revolutionized the treatment of rheumatoid arthritis patients. Mild lupus-like reactions that abated with drug cessation have previously been described as adverse effects. We present a novel 34 year-old RA patient who developed Libman-Sacks endocarditis and symptomatic heart failure after treatment with an anti-TNF agent. METHODS: Case discussion; review of the literature. RESULTS: This RA patient had a transthoracic echo (TTE) prior to infliximab infusions that documented mild mitral valve regurgitation but no valvulopathy. After one year of infliximab infusions, she presented with clear physical signs (high fever, malar rash) and serologic signs of lupus: new anemia (Hb 7.6), mild leukopenia (wbc 4) and thrombocytopenia (plt 133), high titer anti-dsDNA antibodies (1:2560) and antihistone IgG Ab (9.7), low C3, low C4. Her transesophageal echo (TEE) revealed moderate-severe mitral regurgitation and moderate thickening of the anterior mitral leaflets consistent with valvulitis or Libman-Sacks endocarditis. For treatment, she required pulse intravenous steroids and cyclophosphamide. CONCLUSIONS: Given the temporal relation of infliximab institution and the patient’s symptoms, we believe that infliximab was central to either unmasking or inducing this patient’s lupus. These anti-TNF agents may alter the milieu of apoptotic cell clearance. They may cause the release of nuclear autoantigens which drive the production of anti-dsDNA antibodies in genetically susceptible people. They may also inhibit cytotoxic T cells which suppress autoreactive B cells that are central to the pathogenesis of lupus. We believe this case highlights long-standing concerns regarding use of these drugs in patients with preexisting high-titer ANA, especially if concern for concomitant lupus exists. Funding: Baylor College of Medicine
SATURDAY
Abstracts S19
J ALLERGY CLIN IMMUNOL VOLUME 117, NUMBER 2
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ABR and DPOAE in Tubulin Based Induced Autoimmune Hearing Loss M. Habiby Kermany, B. Zhou, M. Yoon, T. Yoo; Allery/Immunology, University of Tennessee, Memphis, TN. RATIONALE: Auditory brainstem responses (ABR) is used for detecting electrical signals of neural transmissions from the inner ear hair cells to central auditory nuclei in the brain, while distortion product of otoacoustic emission (DPOAE) is used for testing functional status of the cochlear hair cells. DPOAE tests the function of cochlear structures. The combination of ABR and DPOAE provide detailed information on physiological defects in auditory pathway. Previous studies show that tubulin is a major constituent protein of microtubules, which are prominent structures in the sensory and supporting cells of the inner ear and is an autoantigen to the inner ear. METHODS: In current study, Balb/C mice presented autoimmune sensory neural hearing loss after immunization with high dose purified tubulin. Six weeks after the second booster, the sensorineural hearing loss was determined by elevation of ABR threshold in alternative polarity clicks and three different frequency levels: low (8KHz) middle (16KHz) and high (32KHz). RESULTS: ABR pick amplitude reductions show significant (P<0.05 mice# 28) as well as significant pick latencies. DPOAE also show significant elevation of threshold in low (8KHz) middle (16KHz) and high (32KHz) frequencies respectively (P<0.05 mice# 28). Degenerated spiral ganglion and cochlear hair cells were found in the inner ears under light microscopic assay. CONCLUSIONS: These results support studies which demonstrate that tubulin induces experimental autoimmune hearing loss in mice and the conclusion that tubulin is an autoantigen to inner ear. Electrophysiology
74
data also reveals that this autoimmune damage affects the entire cochlea, from apical to basal turn (Low ~ High frequencies). Functional Regulation of Normal and SLE Plasma Cells by DCC (Deleted in Colon Cancer) and its Ligand Netrin-1 P. L. Lugar1, R. Slota1, R. T. Fischer1, D. Withers1, P. Pisitkun1, P. E. Lipsky2, A. C. Grammer1; 1Niams, dhhs, NIH, Bethesda, MD, 2Niams, dhhs, Autoimmunity Branch, NIH, Bethesda, MD. RATIONALE: Human B cell populations were examined for the expression of Netrin-1 and DCC, a gene that resides in the 18q12-q21 SLE (Sytemic Lupus Erythematosus) susceptibility locus and has been linked to several autoimmune diseases including SLE. Netrin-1 is a soluble ligand for DCC and has been reported to be a chemoattractant for DCCexpressing cells. METHODS: To examine the potential role of DCC and Netrin-1 in normal and autoimmune human B cell function, quantitative PCR, microarray, multiparameter flow cytometry and immunohistology were used to examine differential expression and gene targets of the Netrin1- DCC interaction. RESULTS: Both DCC and Netrin-1 were highly expressed by plasma cells from tonsil and SLE peripheral blood. By immunohistological analysis of tonsillar tissue, DCC antibody identifies plasma cells with a typical clockwork pattern in situ. Stimulation of highly purified tonsillar with Netrin-1 induces changes in cytokine receptors, chemokine receptors and immunoglobulin itself. CONCLUSIONS: Together, these results indicate that Netrin-1 interacts directly with DCC expressed on plasma cells to regulate differentiation and function. Dysregulation of DCC function may play a role in the pathogenicity of diseases that are mediated by abnormal plasma cell function such as SLE.
75
76
Infliximab Related Lupus and Associated Valvulitis
T. Chadha, J. E. Hernandez; Baylor College of Medicine, Houston, TX. RATIONALE: Anti-TNF agents have revolutionized the treatment of rheumatoid arthritis patients. Mild lupus-like reactions that abated with drug cessation have previously been described as adverse effects. We present a novel 34 year-old RA patient who developed Libman-Sacks endocarditis and symptomatic heart failure after treatment with an anti-TNF agent. METHODS: Case discussion; review of the literature. RESULTS: This RA patient had a transthoracic echo (TTE) prior to infliximab infusions that documented mild mitral valve regurgitation but no valvulopathy. After one year of infliximab infusions, she presented with clear physical signs (high fever, malar rash) and serologic signs of lupus: new anemia (Hb 7.6), mild leukopenia (wbc 4) and thrombocytopenia (plt 133), high titer anti-dsDNA antibodies (1:2560) and antihistone IgG Ab (9.7), low C3, low C4. Her transesophageal echo (TEE) revealed moderate-severe mitral regurgitation and moderate thickening of the anterior mitral leaflets consistent with valvulitis or Libman-Sacks endocarditis. For treatment, she required pulse intravenous steroids and cyclophosphamide. CONCLUSIONS: Given the temporal relation of infliximab institution and the patient’s symptoms, we believe that infliximab was central to either unmasking or inducing this patient’s lupus. These anti-TNF agents may alter the milieu of apoptotic cell clearance. They may cause the release of nuclear autoantigens which drive the production of anti-dsDNA antibodies in genetically susceptible people. They may also inhibit cytotoxic T cells which suppress autoreactive B cells that are central to the pathogenesis of lupus. We believe this case highlights long-standing concerns regarding use of these drugs in patients with preexisting high-titer ANA, especially if concern for concomitant lupus exists. Funding: Baylor College of Medicine
SATURDAY
Abstracts S19
J ALLERGY CLIN IMMUNOL VOLUME 117, NUMBER 2