Síndrome de Hiper-IgM

Descrição Geral

Epidemiologia

• Grupo muito raro de doenças
• Prevalência:
  • A síndrome de hiper-IgM ligada ao X afeta aproximadamente 2 em cada 1 milhão de rapazes recém-nascidos, representando 70% dos casos de hiper-IgM.
  • As formas autossómicas recessivas de hiper-IgM afetam menos de 1 em cada 1 milhão de pessoas.

Fisiopatologia

• O ligante CD40 CD40 Members of the tumor necrosis factor receptor superfamily with specificity for CD40 ligand. They are found on mature B-lymphocytes, some epithelial cells; and lymphoid dendritic cells. Evidence suggests that CD40-dependent activation of B-cells is important for generation of memory B-cells within the germinal centers. Mutations in the CD40 antigen gene result in hyper-igm immunodeficiency syndrome, type 3. Signaling of the receptor occurs through its association with tnf receptor-associated factors. Hyper-IgM Syndrome é encontrado na superfície das células T e liga-se ao seu recetor na membrana das células B, que produzem anticorpos.
• O CD40 CD40 Members of the tumor necrosis factor receptor superfamily with specificity for CD40 ligand. They are found on mature B-lymphocytes, some epithelial cells; and lymphoid dendritic cells. Evidence suggests that CD40-dependent activation of B-cells is important for generation of memory B-cells within the germinal centers. Mutations in the CD40 antigen gene result in hyper-igm immunodeficiency syndrome, type 3. Signaling of the receptor occurs through its association with tnf receptor-associated factors. Hyper-IgM Syndrome defeituoso leva a uma interação deficiente entre células T e células B e a alterações na resposta imune humoral.
• As células B são incapazes de mudar de classe, resultando numa superprodução de anticorpos IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions e uma subprodução de IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions, IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis e IgE IgE An immunoglobulin associated with mast cells. Overexpression has been associated with allergic hypersensitivity. Immunoglobulins: Types and Functions. Consequentemente, os doentes:
  • Produzem anticorpos IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions em excesso
  • Subproduzem IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions, IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis e IgE IgE An immunoglobulin associated with mast cells. Overexpression has been associated with allergic hypersensitivity. Immunoglobulins: Types and Functions
  • Sofrem uma maturação deficiente da afinidade dos anticorpos
  • Tornam-se vulneráveis a infeções bacterianas, particularmente bactérias encapsuladas e toxinas

Classificação

Existem várias condições que pertencem à síndrome de hiper-IgM. Devido à raridade da síndrome, apenas as causas mais MAIS Androgen Insensitivity Syndrome comuns são mencionadas abaixo.

Deficiência de ligante CD40 CD40 Members of the tumor necrosis factor receptor superfamily with specificity for CD40 ligand. They are found on mature B-lymphocytes, some epithelial cells; and lymphoid dendritic cells. Evidence suggests that CD40-dependent activation of B-cells is important for generation of memory B-cells within the germinal centers. Mutations in the CD40 antigen gene result in hyper-igm immunodeficiency syndrome, type 3. Signaling of the receptor occurs through its association with tnf receptor-associated factors. Hyper-IgM Syndrome (CD40L)

• Imunodeficiência combinada
• Forma mais MAIS Androgen Insensitivity Syndrome comum de síndrome hiper-IgM
• Transmissão hereditária ligada ao X
• Interação comprometida entre células T CD4+ ativadas que expressam CD40L e células que expressam CD40 CD40 Members of the tumor necrosis factor receptor superfamily with specificity for CD40 ligand. They are found on mature B-lymphocytes, some epithelial cells; and lymphoid dendritic cells. Evidence suggests that CD40-dependent activation of B-cells is important for generation of memory B-cells within the germinal centers. Mutations in the CD40 antigen gene result in hyper-igm immunodeficiency syndrome, type 3. Signaling of the receptor occurs through its association with tnf receptor-associated factors. Hyper-IgM Syndrome

Deficiência de citidina desaminase induzida por ativação (AID, pela sigla em inglês)

• Imunodeficiência humoral
• 2ª forma mais MAIS Androgen Insensitivity Syndrome comum de síndrome de hiper-IgM
• Hereditariedade autossómica recessiva

Deficiência de CD40 CD40 Members of the tumor necrosis factor receptor superfamily with specificity for CD40 ligand. They are found on mature B-lymphocytes, some epithelial cells; and lymphoid dendritic cells. Evidence suggests that CD40-dependent activation of B-cells is important for generation of memory B-cells within the germinal centers. Mutations in the CD40 antigen gene result in hyper-igm immunodeficiency syndrome, type 3. Signaling of the receptor occurs through its association with tnf receptor-associated factors. Hyper-IgM Syndrome

• Imunodeficiência combinada
• Muito menos comum que a deficiência de CD40L e AID
• Hereditariedade autossómica recessiva
• Interação comprometida entre células T CD4+ ativadas que expressam CD40L e células que expressam CD40 CD40 Members of the tumor necrosis factor receptor superfamily with specificity for CD40 ligand. They are found on mature B-lymphocytes, some epithelial cells; and lymphoid dendritic cells. Evidence suggests that CD40-dependent activation of B-cells is important for generation of memory B-cells within the germinal centers. Mutations in the CD40 antigen gene result in hyper-igm immunodeficiency syndrome, type 3. Signaling of the receptor occurs through its association with tnf receptor-associated factors. Hyper-IgM Syndrome

Apresentação Clínica

A idade média de início da síndrome de hiper-IgM é aproximadamente aos 2 anos. Muitas vezes, leva mais MAIS Androgen Insensitivity Syndrome alguns anos para que os doentes sejam diagnosticados com a doença. Os possíveis sinais e sintomas incluem:

• Infeções sinopulmonares recorrentes na infância, causadas principalmente por bactérias encapsuladas ( Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pneumoniae e Haemophilus influenzae Haemophilus Influenzae A species of Haemophilus found on the mucous membranes of humans and a variety of animals. The species is further divided into biotypes I through viii. Haemophilus)
• Infeções oportunistas, especialmente:
  • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia por Pneumocystis jirovecii ( PCP PCP Pneumocystis jiroveci is a yeast-like fungus causing pneumocystis pneumonia (PCP) in immunocompromised patients. Pneumocystis pneumonia is spread through airborne transmission and classically affects patients with AIDS, functioning as an AIDS-defining illness. Patients may present with insidious onset of fever, chills, dry cough, chest pain, and shortness of breath. Pneumocystis jirovecii/Pneumocystis Pneumonia (PCP), pela sigla em inglês)
  • Infeção pulmonar por histoplasma Histoplasma Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. The fungus exists as a mold at low temperatures and as yeast at high temperatures. H. capsulatum is the most common endemic fungal infection in the US and is most prevalent in the midwestern and central states along the Ohio and Mississippi River valleys. Histoplasma/Histoplasmosis
  • Gastroenterite por Cryptosporidium Cryptosporidium A genus of coccidian parasites of the family cryptosporidiidae, found in the intestinal epithelium of many vertebrates including humans. Hyper-IgM Syndrome, que conduz a doença do trato biliar, cirrose e colangiocarcinoma
  • Infeção GI por Giardia Giardia A genus of flagellate intestinal eukaryotes parasitic in various vertebrates, including humans. Characteristics include the presence of four pairs of flagella arising from a complicated system of axonemes and cysts that are ellipsoidal to ovoidal in shape. Nitroimidazoles lamblia
  • Hepatite C
• Doenças malignas (hepatocarcinoma, colangiocarcinoma e tumores neuroectodérmicos periféricos do trato gastrointestinal e do pâncreas)
• Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia
• Doenças autoimunes
• Hipotiroidismo
• Artrite
• Encefalopatia (degenerativa)
• Diarreia crónica e atraso no crescimento

Diagnóstico

Alterações laboratoriais

• Níveis séricos baixos de IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis, IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions e IgE IgE An immunoglobulin associated with mast cells. Overexpression has been associated with allergic hypersensitivity. Immunoglobulins: Types and Functions
• Níveis séricos normais ou elevados de IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions
• Resposta insuficiente ou ausente dos anticorpos a certos antigénios proteicos (tétano, difteria e Haemophilus influenzae Haemophilus Influenzae A species of Haemophilus found on the mucous membranes of humans and a variety of animals. The species is further divided into biotypes I through viii. Haemophilus) e polissacarídeos ( Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pneumoniae)

Testes Testes Gonadal Hormones de confirmação

• Análise de ADN para confirmar a mutação de CD40 CD40 Members of the tumor necrosis factor receptor superfamily with specificity for CD40 ligand. They are found on mature B-lymphocytes, some epithelial cells; and lymphoid dendritic cells. Evidence suggests that CD40-dependent activation of B-cells is important for generation of memory B-cells within the germinal centers. Mutations in the CD40 antigen gene result in hyper-igm immunodeficiency syndrome, type 3. Signaling of the receptor occurs through its association with tnf receptor-associated factors. Hyper-IgM Syndrome
• Citometria de fluxo a demonstrar expressão diminuída ou ausente da proteína ligante CD40 CD40 Members of the tumor necrosis factor receptor superfamily with specificity for CD40 ligand. They are found on mature B-lymphocytes, some epithelial cells; and lymphoid dendritic cells. Evidence suggests that CD40-dependent activation of B-cells is important for generation of memory B-cells within the germinal centers. Mutations in the CD40 antigen gene result in hyper-igm immunodeficiency syndrome, type 3. Signaling of the receptor occurs through its association with tnf receptor-associated factors. Hyper-IgM Syndrome, na superfície das células T

Tratamento e Prognóstico

Tratamento

• Deficiência de CD40L e CD40 CD40 Members of the tumor necrosis factor receptor superfamily with specificity for CD40 ligand. They are found on mature B-lymphocytes, some epithelial cells; and lymphoid dendritic cells. Evidence suggests that CD40-dependent activation of B-cells is important for generation of memory B-cells within the germinal centers. Mutations in the CD40 antigen gene result in hyper-igm immunodeficiency syndrome, type 3. Signaling of the receptor occurs through its association with tnf receptor-associated factors. Hyper-IgM Syndrome:
  • Terapêutica de reposição de imunoglobulinas → reduz o risco de bronquiectasias e infeções
  • Transplante alogénico de células hematopoiéticas (TCH): abordagem curativa
  • Monitorização: avaliação regular Regular Insulin dos parâmetros hepáticos mais MAIS Androgen Insensitivity Syndrome ultrassonografia
• Deficiência de AID:
  • Terapêutica de reposição de imunoglobulinas → reduz o risco de bronquiectasias e infeções
  • TCH: abordagem curativa
  • Monitorização: exames regulares para monitorizar a presença de bronquiectasias e doenças linfoproliferativas

Prognóstico

• Deficiência de CD40L e CD40 CD40 Members of the tumor necrosis factor receptor superfamily with specificity for CD40 ligand. They are found on mature B-lymphocytes, some epithelial cells; and lymphoid dendritic cells. Evidence suggests that CD40-dependent activation of B-cells is important for generation of memory B-cells within the germinal centers. Mutations in the CD40 antigen gene result in hyper-igm immunodeficiency syndrome, type 3. Signaling of the receptor occurs through its association with tnf receptor-associated factors. Hyper-IgM Syndrome:
  • As causas de morte mais MAIS Androgen Insensitivity Syndrome comuns são as infeções, a doença hepática e as neoplasias.
  • A expectativa de vida é mais MAIS Androgen Insensitivity Syndrome afetada pela presença e gravidade da doença hepática.
  • Cerca de 60% dos doentes vivem até os 20 anos de idade.
  • O transplante de células hematopoiéticas aumenta a sobrevida para 90% aos 20 anos de idade.
• Deficiência de AID:
  • Melhor prognóstico do que a deficiência de CD40L e CD40 CD40 Members of the tumor necrosis factor receptor superfamily with specificity for CD40 ligand. They are found on mature B-lymphocytes, some epithelial cells; and lymphoid dendritic cells. Evidence suggests that CD40-dependent activation of B-cells is important for generation of memory B-cells within the germinal centers. Mutations in the CD40 antigen gene result in hyper-igm immunodeficiency syndrome, type 3. Signaling of the receptor occurs through its association with tnf receptor-associated factors. Hyper-IgM Syndrome
  • A terapêutica regular Regular Insulin com reposição de imunoglobulinas e o tratamento precoce de infeções melhoram significativamente o prognóstico.

Diagnóstico Diferencial

• Agamaglobulinemia ou hipogamaglobulinemia: condição com ausência ou níveis extremamente baixos de imunoglobulinas. Os 3 principais tipos descritos são ligado ao X, de início precoce e de início tardio. Os doentes apresentam infeções recorrentes e não têm amígdalas e adenoides. O diagnóstico é realizado através da constatação de doses reduzidas de imunoglobulinas séricas e de testes Testes Gonadal Hormones genéticos. O tratamento inclui reposição de imunoglobulinas.
• Imunodeficiência comum variável (ICV): Uma das doenças de imunodeficiência primária mais MAIS Androgen Insensitivity Syndrome comuns causada por alteração da maturação de células B e da produção de imunoglobulinas. A causa da ICV permanece desconhecida na maioria dos casos. Os doentes podem apresentar infeções recorrentes, hiperplasia linfoide, esplenomegalia e neoplasias. O diagnóstico inclui o doseamento de imunoglobulinas séricas e baixa resposta às vacinas.