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IgG4-Related Disease Manifesting as Hypocomplementemic Tubulointerstitial Nephritis: A Rare Case Report and Literature ReviewBhattad, Pradnya Brijmohan, Joseph, David L., Peterson, Eric 01 January 2020 (has links)
Immunoglobulin G4–related disease (IgG4-RD) is a chronic fibrosing inflammatory systemic disorder that has been recognized relatively recently in the medical literature. Little is known about the exact disease pathogenesis and epidemiology. IgG4-RD may be asymptomatic or may have minimal symptoms or involve multiple organs with overt symptoms. The different phenotypes of IgG4-RD can lead to delayed or incorrect diagnosis. We report the case of a 66-year-old male with coal worker’s pneumoconiosis who presented with progressive kidney disease and was diagnosed with tubulointerstitial nephritis due to IgG4-RD. The patient was noted to have progressive kidney disease, skin involvement, worsening interstitial lung disease, complete vision loss in the left eye, and retroperitoneal fibrosis. Serologic workup revealed elevated inflammatory markers, IgG4 and IgG1 levels, and hypocomplementemia. A tissue biopsy helped us establish a definitive diagnosis of IgG4-RD and initiate treatment with glucocorticoids to prevent further progression of kidney disease and other end-organ damage.
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Potential mechanisms in MuSK-myasthenia gravisKoneczny, Inga January 2014 (has links)
Autoimmunity is a failure to tolerate circulating or cell surface expressed self antigens,leading to activation of the immune system and attack of self tissues. Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a disease caused by antibodies to MuSK and hallmarked by fatigable muscle weakness. MuSK is a tyrosine kinase that interacts with low-density lipoprotein receptor-related protein 4 (LRP4), resulting in maintenance of the high density of acetylcholine receptors (AChRs) at the neuromuscular junction; this high density is essential for efficient transmission of signals from nerve to muscle, and MuSK antibodies impair this transmission. MuSK antibodies are predominantly IgG4, a subclass that does not induce immunological damage. Thus how these antibodies cause neuromuscular junction dysfunction is not clear. Potential mechanisms of the MuSK antibodies were explored in in vitro experiments. Plasmas from fourteen MuSK-MG patients were studied. IgG antibodies and IgG subclass profiles were measured with flow cytometry. Total IgG, Fabs, IgG4 and IgG1-3 subclass antibodies were prepared and purified; these were used to investigate the effects on MuSK surface expression, binding of LRP4 to MuSK, and agrin-LRP4-MuSK-induced AChR clustering in C2C12 mouse myotubes. No evidence for MuSK endocytosis by MuSK IgG, IgG1-3 or IgG4 antibodies was found. The predominant IgG4 subclass, and the monovalent IgG Fabs, blocked binding between LRP4 and MuSK but both IgG4 and IgG1-3 subclass antibodies were equally able to disperse pre-formed and newly-induced AChR clusters in C2C12 myotubes. The block of LRP4-MuSK interaction by IgG4 antibodies is likely to be a major pathogenic mechanism in MuSK-MG, which may lead to disrupted signal transduction, reduced AChR aggregation and neuromuscular transmission failure at the neuromuscular junction. In addition, MuSK IgG1-3, until now described as nonpathogenic, may also contribute to the reduced AChR density and neuromuscular dysfunction in MuSK-MG. These results provide new evidence concerning the pathogenic antibodies and their mechanisms in MuSK-MG.
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Eczema in young children : aspects of clinical investigation and treatmentNorrman, Gunilla January 2007 (has links)
Bakgrund: Eksem förekommer hos 10-20% av barn i hela världen. En tredjedel av barnen med eksem har födoämnesallergi. Hos de flesta växer födoämnesallergin bort innan skolåldern. Förbättrat kliniskt omhändertagande och bättre förståelse av hur klinisk tolerans uppkommer är viktiga mål för forskning inom barnmedicin. Studieupplägg: Denna doktorsavhandling baseras på studier av två grupper av barn. Den första är en stor grupp med misstänkt allergi som undersökts med pricktest vid ett tillfälle. Den andra gruppen består av små barn med eksem och misstänkt födoämnesallergi. Barnen påbörjade studien innan två års ålder och har sedan följts över tid till fyra och ett halvt års ålder. Säkerhet vid pricktest: 5908 barn med en medelålder på 6 år och 5 månader, undersöktes med pricktest (SPT). Sju barn (0,12 %) reagerade med generaliserad allergisk reaktion (GAR), och behövde antiallergisk medicinering. Sju barn reagerade vasovagalt (VVR) med svimning eller ”nära-svimning”. Riskfaktorer för GAR var ålder <1 år (RR 6,28) och aktivt eksem (RR 16,98). Risken för VVR var högst hos tonårsflickor och barn/ungdomar undersökta med många allergen (många prickar) samtidigt, oavsett om de var positiva eller inte. Effekt av lokalbehandling och födoämneselimination hos spädbarn med eksem: 123 barn, 52 flickor och 71 pojkar deltog i studien. Åldern varierade mellan 1-24 månader, med en medelålder på 8,4 månader vid studiens början. Kraven för att få delta var eksem och/eller misstänkt födoämnesallergi. Diagnos av eksem gjordes med stöd av Hanifin och Rajkas kriterier. Eksemgrad bedömdes med instrumentet SCORAD. Barnen bedömdes vid två tillfällen med ca sex veckors mellanrum. 62 % av barnen hade positiv pricktest för födoämnen. SCORAD-värdena i gruppen med positiv pricktest var högre än i gruppen med negativ pricktest, barnen som var födoämnessensibiliserade hade alltså svårare eksem. Efter sex veckors behandling; födoämneselimination+ lokalbehandling hos SPTpositiva barn; endast lokalbehandling hos SPT-negativa barn; var det ingen skillnad i eksemens svårighetsgrad mellan de två grupperna. Både födoämnessensibiliserade och icke födoämnessensibiliserade förbättrades signifikant av behandling. En grupp med negativ pricktest, men med påvisade antikroppar mot födoämnen i blodet (analyserade först i efterhand), som behandlades enbart med lokalbehandling förbättrade sina eksem lika mycket som de barn som också ställts på eliminationskost. Antikroppar i blod och saliv i relation till toleransutveckling: Serumnivåer av total- samt ägg- och mjölkspecifika antikroppar av IgE, IgG1 och IgG4 analyserades. I saliv analyserades totalnivåer av sekretoriskt IgA samt specifikt IgA mot mjölk och ägg. Prover togs vid studiens början, efter sex veckor samt vid 4,5 års ålder. Barn som var sensibiliserade mot mjölk och/eller ägg, men som tålde dessa födoämnen vid 4,5 års ålder hade högre IgG4 nivåer och högre IgG4/IgE-kvot vid studiens början, än de barn som ej uppnått tolerans. De högsta IgG4/IgE-kvoterna sågs hos barnen med negativt pricktest men positivt specifikt IgE i blod. Under den första korta observationsperioden på sex veckor sågs ingen påverkan på barnens antikroppsnivåer. Recept/metodutvecklande och resultat av öppna och dubbel-blinda placebokontrollerade födoämnesprovokationer: Efter recept och metodutveckling för födoämnesprovokationer med mjölk och ägg, utfördes 52 provokationer på 39 barn. Fyra barn, alla provocerade blint, reagerade på provokationen. Generella slutsatser: Risken för generaliserade allergiska reaktioner vid pricktest är liten hos barn och tonåringar, men den finns. Riskfaktorer är låg ålder och aktivt eksem. Vasovagala reaktioner är lika vanliga som generaliserade allergiska reaktioner. Lokalbehandling/smörjning ger signifikant förbättring av eksem. Elimination av födoämnen kanske inte är nödvändigt hos eksembarn med sensibilisering för mjölk och ägg under förutsättning att hudvården sköts noga. Höga IgG4/IgE-kvoter av specifika antikroppar mot födoämnen kan vara associerat med snabbare toleransutveckling, och kan stödja idén med fortsatt allergenexponering hos födoämnessensibiliserade barn. Recept på beredningar som väl maskerar komjölk och ägg, vid öppna och blindade födoämnesprovokationer, är en god hjälp vid provokationer av små barn som ofta är misstänksamma mot nya smaker och konsistenser av mat. / Background: Eczema affects at least 20 % of children worldwide, and 1/3 of them also have food allergy. In most children, the food allergy is temporary. Improved clinical management and better understanding of etiological mechanisms underlying the tolerance development are target issues in paediatric research. Study design: The thesis is based on two study groups. The first is a large group of children with suspected allergy investigated with skin prick test in a cross-sectional study. The second group is a cohort of infants with eczema and/or suspected food allergy before 2 years of age, investigated prospectively with follow-up to 4.5 years of age. Safety of skin prick test (SPT): 5908 children with a mean age of 6.4 years (range: 1 month – 18 years) were investigated with SPT. Seven children, i.e. 0.12%, displayed a generalized allergic reaction (GAR), necessitating pharmacological treatment. Seven children showed a vasovagal reaction (VVR). Risk factors for GAR were age < 1 year (RR 6.28) and eczema (RR 16.98). The risk for VVR was highest among female adolescents, and children investigated with multiple skin pricks. The effect of skin care and food elimination on eczema in infants: 123 children, 52 girls and 71 boys, with a mean age of 8.4 months (range: 1-24 months) were recruited due to eczema and/or suspected food allergy. For diagnosis of eczema, the Hanifin and Rajka criteria were used, and for scoring of eczema severity SCORAD. The infants were investigated twice with an interval of 6 weeks. 62% showed positive SPTs. The SCORAD was higher among the sensitized children before treatment compared to not sensitized children. After treatment, i.e. skin care for all and elimination diet for sensitized children, there was no difference regarding eczema severity. Both SPT-positive and SPT-negative children decreased their SCORAD values significantly after treatment. A SPT-negative subgroup, with circulating specific IgE to milk/egg, was only treated with skin care, but these children improved their eczema to the same extent as those also treated with an elimination diet. Serum and salivary antibodies and achievement of tolerance Analyses were performed regarding: serum levels of total and egg- and milk-specific IgE antibodies, IgG1 and IgG4 antibodies to β-lactoglobulin (BLG) and ovalbumin (OVA); and salivary levels of total IgA, total SIgA and salivary IgA antibodies to OVA and BLG. Samples were drawn at inclusion, after 6 weeks of intervention (skin care, elimination diet), and at 4.5 years of age. Children sensitized to egg and/or milk who had developed tolerance at 4 ½ years of age had higher levels of IgG4 antibodies to OVA and BLG and also higher IgG4/IgE ratios on inclusion in the study, than those who remained non-tolerant. The highest IgG4/IgE ratios were found in children with circulating IgE antibodies to egg and/or milk but negative SPT on inclusion. The six-week treatment period did not significantly affect the levels of serum and salivary antibodies. Recipes and outcomes of open and double-blinded food challenges in children: After development of recipes for open and blinded challenge with cow’s milk and egg, 52 challenges were performed in 39 children. 4 children, challenged blindly, had a positive outcome of the challenge. General conclusions: The risk for generalized allergic reactions at SPT is low among children and teenagers, but allergic reactions do occur, and low age and eczema are risk factors. Vasovagal reactions occur as often as allergic reactions. Skin care gives significant improvement of eczema severity. Elimination diet may not be needed in infants with sensitization to milk and/or egg, provided that the skin care is adequate. High ratios of serum IgG4/IgE antibodies to food allergens may be associated with faster achievement of clinical tolerance, and may support the concept of benefit from continuing allergen exposure in sensitized children. Recipes for masking of cow’s milk and egg in open or blinded food challenges may help to accomplish challenges in young children, often suspicious to unfamiliar tastes or textures.
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Atividade bloqueadora de anticorpos IgG específicos purificados de soros de pacientes atópicos a ácaros sobre a reatividade de IgE a Dermatophagoides pteronyssinus por ELISA inibiçãoSiman, Isabella Lima 22 June 2013 (has links)
One of the purposes of allergen-specific immunotherapy (SIT) is to modulate the humoral
immune response against allergens with significant increases in allergen-specific IgG1 and
IgG4 levels. These antibodies are associated with blocking activity by preventing IgE binding
to allergen and leading to reduced inflammatory responses. This study aimed to investigate in
vitro blocking activity of allergen-specific IgG antibodies on IgE reactivity to D.
pteronyssinus (Dpt) in sera from atopic patients. Dpt-specific IgG antibodies were obtained
from atopic sera and irrelevant IgG from non-atopic sera. IgG antibodies were purified by
ammonium sulfate precipitation followed by Protein-G affinity chromatography and evaluated
with regards to purity by SDS-PAGE and immunoreactivity by slot-blot and immunoblot
assays. The blocking activity was evaluated by inhibition ELISA. The electrophoretical
profile after salting-out precipitation showed an enrichment of high molecular weight proteins
in the precipitated fraction and strongly stained bands in the ligand fraction after
chromatography, compatible with molecular weight of human IgG. It was detected strong
immunoreactivity to IgG, negligible to IgA, and no reactivity to IgE and IgM. Dpt-specific
IgG fraction was capable to significantly reduce levels of IgE anti-Dpt, resulting in 35-51%
inhibition of IgE reactivity to Dpt in atopic patient sera. Allergen-specific IgG antibodies
purified using available and standardized methodology are able to inhibit IgE reactivity to Dpt
allergen extract. In addition to the clinical symptoms improvement (subjective parameter),
this approach reinforces that the intermittent measurement of serum allergen-specific IgG
antibodies will be an important objective laboratorial parameter that will help specialists to
follow their patients under SIT. / Uma das propostas da imunoterapia alérgeno específica é a de modular a resposta imune
humoral contra alérgenos, com aumento significativo nos níveis de IgG1 e IgG4 específicos.
Esses anticorpos estão associados com uma atividade bloqueadora, impedindo a ligação de
anticorpos IgE ao alérgeno e levando a uma redução nas respostas inflamatórias. Esse estudo
objetivou investigar a atividade bloqueadora, in vitro, de anticorpos IgG específicos sobre a
reatividade de IgE a D. pteronyssinus (Dpt) em soros de pacientes atópicos. Anticorpos IgG
específicos foram obtidos de soros de pacientes atópicos, e IgG irrelevante a partir de soros de
não atópicos, e depois purificados por precipitação com sulfato de amônio, seguido de
cromatografia de afinidade em Proteina G-agarose. A pureza desses anticorpos foi avaliada
por SDS-PAGE, a imunoreatividade por ensaios de slot-blot e immunoblot, e a atividade
bloqueadora por ELISA inibição. O perfil eletroforético, após precipitação com sulfato de
amônio, mostrou um enriquecimento de proteínas de alto peso molecular na fração
precipitada,e bandas fortemente coradas na fração ligante após a cromatografia, compatíveis
com o peso molecular de IgG humana. Foi detectada uma forte imunoreatividade para IgG,
leve para IgA, e nenhuma reatividade para IgE e IgM. A Fração IgG específica foi capaz de
reduzir significantemente os níveis de IgE anti-Dpt, resultando em 35-51% de inibição da
reatividade de IgE a Dpt em pools de soros de pacientes atópicos. Anticorpos IgG específicos
purificados, através de uma metodologia disponível e padronizada, são capazes de inibir a
reatividade de IgE ao extrato alergênico Dpt. Além da melhoria da sintomatologia clínica,
considerada um parâmetro subjetivo, essa abordagem reforça que a avaliação intermitente de
anticorpos IgG alérgeno-específicos pode ser uma ferramenta importante, auxiliando
especialistas a acompanharem seus pacientes em processo de imunoterapia específica. / Mestre em Ciências da Saúde
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Reatividade anticórpica IgE, IgG1 e IgG4 específica a antígenos de pólen de Lolium multiflorum (Lam. 1779) em pacientes com polinoseMoreira, Priscila Ferreira de Sousa 22 February 2006 (has links)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Background: Seasonal allergic rhinoconjunctivitis or hay fever is caused due to the
sensitization to pollen allergens, usually from grasses. Lolium multiflorum (Lm) is one of the
most important grass pollen allergens in Southern Brazil.
Objectives: To evaluate three different pollen extraction methods and to analyze IgE, IgG1
and IgG4 responses to Lm pollen antigens in pollinosis patients.
Methods: Three different Lm pollen extracts were prepared (LmPBS extract, Lme-PBS extract
and LmNH4HCO3 extract) and analyzed in 13.5% SDS-PAGE. Serum samples from 62 patients
with seasonal allergic rhinoconjunctivitis and/or asthma (Lm+ group), 30 patients with
perennial allergy rhinitis (Lm- group) and 30 non-atopic subjects (NA) were tested for IgE
reactivity to three Lm extracts by ELISA. Lm-specific IgG1 and IgG4 antibodies were also
evaluated by using LmPBS extract only in ELISA.
Results: By SDS-PAGE, the three extracts were very similar, showing bands ranging from 20
to 100 kDa. By ELISA-IgE, the results revealed higher IgE levels in pollinosis patients when
LmPBS extract was used. LmPBS extract was chosen to evaluate the IgE, IgG1 and IgG4
responses and their levels were higher in the Lm+ patients when compared to Lm and NA
groups. In the Lm+ group, IgE (EI = 17.6) levels were higher than IgG1 (EI = 2.6) and IgG4
(EI = 3.6) levels, while in other groups there were not any differences in the antibody levels.
Conclusions: LmPBS extract was effective in detecting IgE, IgG1 and IgG4 responses to
Lolium multiflorum pollen antigens. These antibody classes are in a higher level in pollinosis
patients when compared to non-sensitized subjects. Lm allergen extracts for in vivo and in
vitro using should be standardized. / Introdução: A rinite alérgica estacional ou doença polínica se deve à sensibilização aos
alérgenos de pólens, geralmente de gramíneas. Lolium multiflorum (Lm) é uma gramínea
com pólens de elevado potencial alergênico, sendo a principal gramínea causadora de
polinose na região Sul do Brasil.
Objetivos: Analisar três diferentes métodos de extração antigênica pela reatividade IgE de
cada extrato e as respostas anticórpicas IgE, IgG1 e IgG4 específicas aos antígenos de
pólen de Lm.
Material e Métodos: Três extratos de pólen de Lm foram preparados (extratos LmPBS, Lme-
PBS e LmNH4HCO3) e analisados por SDS-PAGE a 13,5%. Amostras de soro de 62 pacientes
com rinite alérgica sazonal e/ou asma brônquica (grupo Lm+), 30 pacientes com rinite
alérgica perene (grupo Lm-) e 30 indivíduos não-atópicos (grupo NA) foram testadas para a
reatividade IgE frente aos três extratos por ELISA. Anticorpos IgG1 e IgG4 específicos a Lm
foram avaliados empregando-se somente o extrato LmPBS, por ELISA.
Resultados: O perfil protéico dos extratos foi muito semelhante por SDS-PAGE,
apresentando bandas protéicas de 20 a100 kDa. Níveis de IgE foram maiores em pacientes
com polinose ao se utilizar o extrato LmPBS. O extrato LmPBS foi utilizado para avaliar os
níveis de IgE, IgG1 e IgG4, que foram maiores nos pacientes com polinose que em pacientes
Lm- e indivíduos NA. No grupo Lm+, os níveis médios de IgE (IE = 17,6) foram maiores que
os níveis de IgG1 (IE = 2,6) e IgG4 (IE = 3,6) (p < 0,001).
Conclusões: O extrato LmPBS foi eficiente em detectar as respostas IgE, IgG1 e IgG4 a
antígenos de pólen de Lm. Essas classes de anticorpos estão em níveis maiores em
pacientes com polinose. Extratos antigênicos de Lm para uso in vivo e in vitro devem ser
padronizados. / Mestre em Imunologia e Parasitologia Aplicadas
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Eficácia clínica e alterações na resposta de anticorpos sistêmicos e de mucosa após imunoterapia sublingual em crianças alérgicas a ácaros: um estudo randomizado duplo-cego, controlado com placeboQueirós, Meimei Guimarães Junqueira de 19 August 2011 (has links)
This study aimed to evaluate the clinical efficacy and systemic/mucosal antibody
response changes after sublingual immunotherapy (SLIT) using Dermatophagoides
pteronyssinus (Dpt) allergens with or without bacterial extracts in mite-allergic
children. One-hundred and two patients presenting allergic rhinitis with or without
asthma were selected for a randomized double-blind, placebo-controlled trial and
distributed into three groups: DPT (Dpt allergen extract, n=34), DPT+MRB (Dpt
allergen plus mixed respiratory bacterial extracts, n=36), and Placebo (n=32). Clinical
evaluation and immunological analyses were carried out before and after 12 and 18
months of treatment, including rhinitis/asthma symptom and medication scores, skin
prick test (SPT) to Dpt extract, and measurements of Dpt, Der p 1, Der p 2 specific
IgE, IgG4, and IgG1 in serum and specific IgA in saliva and nasal lavage fluid.
Clinical results showed a significant decline in rhinitis/asthma symptom scores in all
groups, but medication use decreased only in DPT group after 12 months. SPT
results showed no significant changes and SLIT was generally safe, with no severe
systemic reactions. SLIT using Dpt allergen alone induced increased serum IgG4
levels to Dpt, Der p 1 and Der p 2, and increased serum IgG1 and salivary IgA levels
to Dpt and Der p 1. SLIT using DPT+MRB was able to decrease IgE levels to Der p
2, to increase salivary IgA levels to Der p 1, but had no changes on specific IgG4 and
IgG1 levels. In conclusion, clinical improvement was observed both in the SLIT
group and the control, but only active SLIT was able to modulate the
mucosal/systemic antibody responses. These findings support the role of specific
serum IgG4 and IgG1, in addition to salivary IgA, as probable blocking antibodies or
biomarkers of tolerance that may be useful for monitoring the allergen specific
immunotherapy. / Este estudo teve como objetivo avaliar a eficácia clínica e alterações da resposta de
anticorpos sistêmicos e de mucosa após a imunoterapia sublingual (SLIT), utilizando
alérgenos de Dermatophagoides pteronyssinus (Dpt), com ou sem extratos
bacterianos em crianças alérgicas a ácaros. Cento e dois pacientes com rinite
alérgica com ou sem asma foram selecionados para um estudo randomizado duplocego,
controlado por placebo e distribuídos em três grupos: DPT (extrato alergênico
de Dpt, n=34), DPT+MRB (extrato alergênico de Dpt associado com extrato de
bactérias mistas do trato respiratório, n=36), e Placebo (n=32). Avaliação clínica e
análises imunológicas foram realizadas antes do tratamento e após 12 e 18 meses,
incluindo a pontuação de escores de sintomas e medicamentos de rinite/asma, teste
cutâneo (SPT) ao extrato Dpt, e medidas de anticorpos específicos IgE, IgG4 e IgG1
para Dpt, Der p 1, Der p 2 no soro e IgA específicos na saliva e no lavado nasal. Os
resultados clínicos mostraram uma redução significativa nos escores de sintomas de
rinite/asma em todos os grupos, mas o uso de medicamentos diminuiu apenas no
grupo DPT após 12 meses. Resultados de SPT não mostraram mudanças
significativas e SLIT foi geralmente segura, sem reação sistêmica grave. SLIT
usando somente alérgeno Dpt induziu aumento dos níveis de IgG4 para Dpt, Der p 1
e Der p 2 no soro, e aumentou os níveis de IgG1 no soro e salivares de IgA para Dpt
e Der p 1. SLIT usando DPT+MRB foi capaz de diminuir os níveis de IgE para Der p
2, aumentar os níveis salivares de IgA para Der p 1, mas não tiveram alterações nos
níveis de anticorpos específicos de IgG4 e IgG1. Em conclusão, foi observado
melhora clínica tanto no grupo da SLIT como do controle, porém somente na SLIT
com alérgeno foi capaz de modular as respostas de anticorpos sistêmicos e de
mucosa. Estes achados reforçam o papel de anticorpos IgG4 e IgG1 séricos
específicos, além de IgA salivar, como prováveis anticorpos bloqueadores ou
biomarcadores de tolerância que podem ser úteis para monitoramento da
imunoterapia alérgeno-específica. / Doutor em Imunologia e Parasitologia Aplicadas
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