Immune responses to SS-A 52-kDa and 60-kDa proteins and to SS-B 50-kDa protein in mothers of infants with neonatal lupus erythematosus

Mothers who have anti-SS-A/Ro and anti-SS-B/La antibodies have a greater risk of bearing infants with neonatal lupus erythematosus (NLE). However, most mothers with anti-SS-A/Ro and anti-SS-B/La antibodies give birth to infants with no evidence of NLE. We studied mothers who had the combination of clinical evidence of connective tissue disorder, positive antinuclear antibody and positive anti-SS-A/Ro and/or anti-SS-B/La antibodies. We analysed SS-A/Ro and SS-B/La antibody responses to recombinant 60-, 52- and 50-kDa proteins in eight mothers of NLE infants and 19 mothers whose children did not have NLE. Molecular analysis of the anti-SS-A/Ro and anti-SS-B/La antibodies was carried out by enzyme-linked immunosorbent assay using recombinant 60-, 52- and 50-kDa proteins. The mothers of children with cutaneous NLE were all positive for a high titre of 50-kDa protein. Mothers of children with NLE with complete heart block (CHB) were positive for 52- and 60-kDa proteins. We conjecture that anti-SS-B/La antibody influences the development of cutaneous NLE, and that anti-SS-A/Ro antibody influences the development of NLE with CHB.     

Neonatal lupus erythematosus: a review of the racial differences and similarities in clinical, serological and immunogenetic features of Japanese versus Caucasian patients

There has been tremendous interest in neonatal lupus erythematosus (NLE) since the reports of anti‐Ro/SSA antibodies as a diagnostic marker. Recent studies, including ours, have revealed racial differences as well as similarities in the clinical features and immunogenetic backgrounds of Japanese and Caucasian patients with NLE. The frequency of photosensitivity and subacute cutaneous LE lesions is not high in Japanese infants with NLE, which is in sharp contrast to their Caucasian American counterparts. The majority of Japanese infants with NLE develop annular, erythematous or edematous lesions which have also been reported in association with Sjögren's syndrome. The frequency of isolated congenital heart block (CHB) is about 50% in Japanese anti‐Ro/SSA positive neonatal lupus infants; this is similar to the frequency among Caucasians. The HLA‐DR3 phenotype, which is found in the great majority of Caucasian mothers of NLE infants, is absent in Japanese mothers. Finally, both Japanese and Caucasian children with CHB are often identical to their mothers in their alleles of HLA‐DRB1, DQA1 and DQB1 loci.     

The cytotoxic effect of neonatal lupus erythematosus and maternal sera on keratinocyte cultures is complement-dependent and can be augmented by ultraviolet irradiation

Summary To elucidate the role of autoantibodies and ultraviolet (UV) exposure in the pathogenesis of the skin lesions in neonatal lupus erythematostis (NLE). keratinocytes were cultured, as the target cells, from a patient with NLE and from a normal neonate. We demonstrated that the expression of nuclear/cytoplasmic Ro/SSA and La/SSB molecules on to the surface of NLE keratinocytes occurred to a much greater extent than that on normal keratinocytes. A dose of 200 ml/cm² UVB irradiation on NLE keratinocytes induced a 2.5–3-fold increase in Ro/SSA and La/SSB expression compared to non-irradiated cells. Sera derived from both the NLE patient and from his mother exhibited a cytotoxie effect on NLE keratinocytes, but not on control cells, in the presence of complement. Furthermore, the cytotoxieity of the sera was enhanced on UVB-irradiated NLE keratinocytes. whereas it had no cytotoxie efects on UVB-irradiated control cells. This suggests that the abnormal expression of both Ro/SSA and La/SSB on the surface membrane of NLE keratinocytes induces the autoantibodies and complements to injure the cells. This complement-mediated cytotoxic effect can be augmented by UV irradiation, a concept not incompatible with the exacerbation of the skin eruption in sun-exposed skin sites.     

Neonatal Lupus Erythematosus Related to Maternal Leukocytoclastic Vasculitis

Abstract: Neonatal lupus erythemalosus (NLE) is an autoimmune disease whose major findings are skin lesions and congenital heart block. Affected infants have maternal, transplacentally acquired, autoantibodies to Ro/SSA, La/SSB, or U,-RNP antigens. Anti-Ro/SSA is the predominant autoantibody, present in about 95% of cases. Mothers of babies with NLE may be asymptomatic initially or may have Sjógrent syndrome, lupus erythematosus, overlap syndrome or, uncommonly, leukocytoclastic vasculitis. When evaluating a young woman with a cutaneous leucocytoclastic vasculitis, dermatologists should be aware of the possible presence of antibodies related to NLE. If any patient suffering a disorder related to NLE becomes pregnant, testing for autoantibodies and close obstetric prenatal care with fetal echocardiogram is necessary. In cases of fetal bradycardia, treatment with dexamethasone or betamethasone should be considered, as these drugs are accessible to the fetal circulation.     

IgG subclasses in the serum and skin in subacute cutaneous lupus erythematosus and neonatal lupus erythematosus

IgG subclasses differ in their biologic and chemical properties, such as complement fixation, protein and cellular binding, and placental transfer. In this study, IgG subclasses of anti-Ro/SSA antibodies in subacute cutaneous lupus (SCLE) and neonatal lupus (NLE) are examined in the serum and in the skin. IgG subclasses in NLE beginning in utero (NLE-heart disease) are compared to subclasses in NLE beginning after birth (NLE-skin disease). Human skin was grafted onto athymic mice, mice were injected with one of eight anti-Ro/SSA maternal NLE sera (four heart block, four skin disease) or seven anti-Ro/SSA SCLE sera, and grafts were examined for IgG subclasses using monoclonal anti-human IgG subclass reagents in an immunofluorescent technique. Lesional skin was examined from four SCLE patients. IgG1 was the only IgG subclass detected in the grafts and skin lesions. IgG1 was the predominant anti-Ro/SSA IgG subclass detected in SCLE and NLE sera in an ELISA using a synthetic Ro/SSA polypeptide. These studies show that the maternal anti-Ro/SSA autoantibodies in NLE-heart disease sera are predominantly IgG1 and are therefore likely to be present in the fetus at the time of gestation, when heart block usually develops. Second, differences in the clinical presentations of NLE (in utero vs. postnatal disease) cannot be attributed to differences in anti-Ro/SSA IgG subclasses. Finally, the subclass bound in the skin in SCLE is IgG1, a subclass capable of mediating tissue injury via complement or cellular effectors.     

Neonatal lupus erythematosus infants and their mothers: a 10-year retrospective study

BackgroundNeonatal lupus erythematosus (NLE) is a rare disease associated with transplacental transfer of maternal anti-Ro/anti-Sjögren syndrome A antibodies. The most common manifestations are cutaneous erythema and congenital heart block. Mothers of infants with NLE are either asymptomatic or diagnosed with autoimmune disease. The goal of this study is to investigate the clinical manifestation, prognosis, and association with autoimmune disease in NLE babies and their mothers in Taiwan.MethodsMedical records of newborns with NLE and their mothers from two hospitals in Taiwan between January 1999 and January 2009 were reviewed. Twenty-five newborns (one set of twins) and 24 mothers of infants with NLE were included in the study. Clinical data, including characteristics of skin manifestations, the onset of symptoms, and infants' antibody titers, were collected. A diagnosis of NLE was made if the baby had heart block or characteristic skin lesions and maternal antibodies to Sjögren syndrome A/Ro, Sjögren syndrome B/La, or U1 ribonucleoproteins. Questionnaires were used to determine the mother's health status at the time of delivery and in subsequent years.ResultsOf the infants, 84% had typical cutaneous manifestations of NLE, and 16% presented with congenital heart block without skin changes. The cutaneous lesions appeared on average at 21.7 weeks. Thirteen mothers were initially asymptomatic, and the other 11 remained asymptomatic over a mean follow-up period of 3.9 years. Two mothers developed lupus nephritis.ConclusionThere was a lower incidence of observed congenital heart block compared to previously reported NLE studies among Caucasian populations. Most mothers were asymptomatic before the birth of their NLE child, and few developed autoimmune diseases. However, continued follow-up of asymptomatic NLE mothers is recommended due to the chances of developing a life-threatening, systemic autoimmune disease.     

新生儿红斑狼疮5例分析

目的探讨新生儿红斑狼疮(NLE)的诊断和治疗方法。方法对5例NLE患儿的临床表现及实验室检查进行分析,并复习相关文献。结果患儿皮损类似SCLE,局限或全身分布,以颜面、躯干及四肢末端为重,患儿及其母亲ANA、抗Ro/SSA及/或抗La/SSBIgG抗体均阳性,心电图检查未见心脏传导阻滞,未经治疗数周后自然消退。结论根据皮损表现和实验室检查可诊断新生儿红斑狼疮,一般不需治疗。     

Neonatal Lupus Syndrome Associated with Ribonucleoprotein Antibodies

Neonatal lupus erythematosus (NLE) is a rare acquired autoimmune disease caused by transplacental transfer of maternal immunoglobulin G antibodies to the fetus. NLE has well‐recognized cutaneous features and may also manifest in other organs. The majority of cases are associated with Ro/SSA and La/SSB antibodies. Neonatal lupus due to antiribonucleoprotein (RNP) antibodies has rarely been reported. On rare occasions RNP has been found in association with other antibodies. We report a case of NLE occurring solely due to RNP antibodies presenting as varicelliform lesions at birth. We recorded the features in our case and 14 additional cases identified in the literature. It is important to recognize that maternal transfer of RNP antibodies may produce the classic cutaneous features of neonatal lupus. The limited case reports of this condition suggest that manifestations are limited to the skin; specifically, there are no reports of cardiac involvement. The long‐term outcome remains unknown. RNP‐positive, Ro/La‐negative NLE seems to represent a different clinical subset of NLE. The recognition of RNP antibody NLE as a benign condition limited to the skin is helpful in planning antenatal care for subsequent pregnancies.     

Neonatal Lupus Erythematosus in an Infant with Turner Syndrome

Abstract: Neonatal lupus erythematosus (NLE) is characterized by transient, annular cutaneous lesions, congenital heart block, and a variety of systemic or hematologic abnormalities. We describe a white infant girt with onset of skin lesions on the face and scalp at 4 days of age. At age 4 weeks she had generalized, erythematous, scaly, annular skin lesions that underwent spontaneous regression at age 5 months. Her mother had no cutaneous or other lesions, but complement examinations revealed the presence of anti-Ro(SSA) and anti-La(SSB) antibodies, and absence of anti-Sm and anti-RNP antibodies. Karyotyping revealed Turner syndrome (TS) with 45,XO sex chromosome constitution. Ro(SSA) and La(SSB) antibodies were found, and direct immunofluorescence testing on healthy skin was positive. At age 5 months, follow-up immunologic examination of the infant had normal results but the mother still had anti-Ro(SSA) and anti-La(SSB) antibodies. We believe that this is the first reported case of NLE in association with TS.     

Neonatal lupus erythematosus. Report of serological and immunogenetic studies in twins discordant for congenital heart block

Summary Autoantibody, HLA studies and C4 phenotypes were performed on twins discordant for isolated congenital heart block. Serum from the mother and cord blood from the infants revealed Ro(SSA) and La(SSB) antibodies in all three sera. No significant difference in Ro(SSA) antibody titre was noted in the cord blood of either twin when compared with maternal titres, as detected by a sensitive ELISA assay. The infants' mother was HLA-DR3 positive. Both infants had identical HLA and C4 phenotypes. Immunoblot analysis revealed that sera from both mother and infants reacted with the 52-kDa Ro(SSA) macromolecule. Quantitative cord blood IgM levels were not elevated in either twin. This study indicates that placental transfer of anti-Ro(SSA) or anti-La(SSB) alone to the fetus is not sufficient for the expression of congenital complete heart block. We conclude from this experiment of Nature that there must be a second event determining which infant develops complete heart block, but this is unknown at present.     

Significance of tubuloreticular structures forming in Daudi cells cultured with sera from mothers bearing infants with neonatal lupus erythematosus

It is known that infants with neonatal lupus erythematosus (NLE) may be born to mothers whose sera are positive for the anti-Ro/SSA antibody. However, women who have this antibody do not always give birth to children with NLE. We have demonstrated tubuloreticular structures in vascular endothelial cells in the skin lesions of infants with NLE. Tubuloreticular structures could no longer be detected at the site of the lesions once the annular erythema had resolved, and the anti-Ro/SSA antibody test had become negative. The probability of a child being born with NLE was assessed by observing whether tubuloreticular structures were formed in Daudi cells cultured with sera from eight mothers who were anti-Ro/SSA antibody positive. Tubuloreticular structures formed in Daudi cells cultured with sera from four mothers who bore infants with NLE, but not in Daudi cells cultured with sera from four other mothers who bore normal infants. These results suggest that women who are positive for the anti-Ro/SSA antibody have a higher risk of bearing infants with NLE if tubuloreticular structures are formed in Daudi cells cultured with sera from these women, whereas this risk is lower if tubuloreticular structures do not develop in Daudi cells.     

Neonatal lupus erythematosus

We present a case of neonatal lupus erythematosus (NLE) in a black infant presenting with symmetrical depigmented macules on the face resembling vitiligo. NLE is a rare condition affecting newborn infants of mothers who have connective tissue disease, with or without autoantibodies to extractable nuclear antigens Ro (SS-A), La (SS-B) or ribonucleoproteins. Infants present with cutaneous lesions or congenital heart block or both. The skin lesions are usually annular and erythematous and transient and resemble those of subacute cutaneous lupus erythematosus. The presentation of this patient was therefore striking.     

Neonatal lupus erythematosus: 4 cases and clinical review

Neonatal lupus erythematosus (NLE) is an infrequent disease in newborns caused by the transplacental passage of maternal Anti-Ro/SSA, Anti-La/SSB and/or Anti-U1 RNP antibodies. The most common manifestations are cutaneous and cardiac. We carried out a retrospective study of cases of NLE diagnosed in the last 10 years at the Hospital Universitario Insular in Gran Canaria. Complete data was obtained for 4 patients. Three cases had circulating Anti-Ro antibodies in the mother and in the newborns, while in the fourth case they were Anti-RNP. Two mothers were diagnosed with systemic lupus, one with mixed connective tissue disease and the other with leucocytoclastic vasculitis. The skin lesions consisted of urticaria-like and desquamative lesions. One patient presented with ulceration. The histological study of the urticaria-like lesions showed a non-specific perivascular infiltrate; the desquamative lesions were consistent with subacute lupus erythematosus.     

U1RNP positive neonatal lupus erythematosus: association with anti-La antibodies?

Summary Neonatal lupus erythematosus (NLE) is an antibody-mediated disorder most commonly associated with autoantibodies to Ro and/or La antigens. There have been five previous reports describing eight NLE patients with anti-U₁RNP antibody in the absence of anti-Ro and anti-La autoantibodies. We report two cases of anti-U₁RNP antibody-positive NLE, and briefly review the five previous reports. The diagnosis of NLE was based on physical examination and serotogical studies by ELISA, immunodiffusion, and immunoblotting. By conventional immunodiffusion and ELISA, our cases were negative for anti-Ro and anti-La antibodies, and positive for anti-U₁RNP antibody. However, one of the mothers had anti-La antibody detected by immunoblot assay only. All anti-U₁RNP antibody-positive infants had classic cutaneous lesions of NLE, but it is of interest that none had congenital heart block (CHB). Although these infants were negative for anti-Ro and anti-La antibodies with immunodiffusion and EL ISA techniques, these antibodies might be detectable by immunoblotting, as was the case in one of the mothers.     

The relationship between facial annular erythema and anti-SS-A/Ro antibodies in three East Asian women

A distinct annular erythema developed on the cheeks of three East Asian women who had anti-SS-A/Ro (SSA) antibodies. The erythema was characterized by a wide, elevated border and central pallor. Histologically, there was a coat-sleeve-like infiltration of lymphocytes around the blood vessels, appendages, and secretory gland cells in the dermis. Immunohistological analysis clarified that the majority of infiltrating lymphocytes were CD4-positive T cells. Abnormal expression of HLA-DR antigens in the perivascular, appendage, and secretory gland cells in the dermis was also observed. The differential diagnosis of the three patients lay between Sjögren syndrome (SjS), Sjögren/systemic lupus erythematosus overlap syndrome and an asymptomatic clinical state. These results are consistent with recent findings of major histocompatibility complex class II expression on target organs in various autoimmune diseases. Based on these findings, erythema appears to represent a broad cutaneous manifestation of these diseases. Furthermore, the presence of SSA antibodies, aberrant HLA-DR expression, and sun exposure may be responsible for the development of erythema.     

Neonatal lupus erythematosus

Neonatal lupus Erythematosus (NLE) is a disorder characterized by maternal autoantibodies against RNA protein complex, Ro/SSA or SSB/La. These maternal IgG antibodies cross the placenta and potentially lead to fetal tissue damage and the clinical manifestations NLE. NLE is uncommon, affects females more than males, has no race predilection, and involves multiple organs. It has cutaneous manifestations similar to subacute cutaneous lupus erythematosus (SCLE). In addition to skin findings, patients with NLE have a significant risk of congenital heart block (CHB), a potentially fatal complication. Less frequently, hematologic and hepatic abnormalities occur. Approximately half of the reported cases have skin disease and half have CHB. Approximately 10% have both CHB and skin findings. The cutaneous, hematologic, and hepatic abnormalities are transient, clearing by 6 months of age. However, CHB is permanent and requires a pacemaker in many cases. The disorder results from the passive transfer of maternal autoantibodies, anti-RoSSA and anti-La/SSB. Sontheimer and McCauliffe reviewed the pathogenic role of anti-Ro antibody in NLE lesions and summarize evidence supporting its pathogenic role. Additional evidence suggests the possibility that Ro-antigen-specific T-cells may be present in SCLE patients and have the capacity to cause direct injury to the skin. McCuistion and Schoch first suggested this hypothesis in 1954 when they described an infant with LE skin findings born to a mother with systemic lupus erythematosus (SLE). Since this initial observation, a number of researchers have documented the role of maternal autoantibodies in the pathogenesis of this disorder. The true incidence of NLE is not known; however, it is known that NLE accounts for approximately 80% of all cases of CHB, and the incidence of CHB is 1 per 20,000 live births. Therefore, it can be assumed that the incidence of NLE is at least 1 per 12,500 live births.     

Ro/SSA antigen in human epidermis

It has been shown previously by an immunofluorescence technique, that whole serum from patients who have anti-Ro/SSA autoantibodies reacts with a component or components of the epidermis. We have now demonstrated by immunoblotting that the antigen identified in human epidermis by anti-Ro/SSA sera is Ro/SSA antigen, and that Ro/SSA antigen is present both in adult and in neonatal epidermis. The presence of this antigen in tissues which are injured in the anti-Ro/SSA-associated syndromes subacute cutaneous lupus erythematosus and neonatal lupus erythematosus supports the hypothesis that anti-Ro/SSA antibodies react with Ro/SSA antigen in the skin and are important in the initiation of tissue damage.     

Neonatal Lupus Erythematosus: An Unusual Congenital Presentation with Cutaneous Atrophy,Erosions, Alopecia,and Pancytopenia

Abstract: Neonatal lupus erythematosus (NLE) is a rare disorder believed to be caused by the transplacental passage of specific autoantibodies from the mother to the fetus. Affected infants typically present with either characteristic skin lesions developing in the first month or later in life or congenital heart block. We report a very unusual case of NLE that was characterized by congenital skin atrophy, erosions, alopecia, and profound pancytopenia. Ro, La, and RNP antibodies were absent, and the diagnosis was made because of light microscopic and immunofluorescent findings. This case emphasizes that NLE can have widespread congenital skin involvement and suggests that at least some cases are mediated by antibodies other than Ro, La, and RNP.     

Neonatal lupus erythematosus: clinical findings and pathogenesis

Neonatal lupus erythematosus is an uncommon disease associated with maternal autoantibodies to proteins of the Ro/La (SSA/SSB) family. The clinical findings most often reported are third-degree heart block and cutaneous lupus lesions, but a significant number of children have cardiomyopathy, hepatobiliary disease, or hematologic cytopenias. The consistent presence of maternal autoantibodies and the transient nature of the disease implicate maternal autoantibodies as the cause of the disease, and developing animal models support the concept that the autoantibodies are pathogenic. Only a minority of babies exposed to the autoantibodies develop disease, however, and mothers and their babies have different disease manifestations. Thus, additional factors are likely to be important in determining disease expression.     

Neonatal lupus erythematosus

Neonatal lupus erythematosus is associated with cutaneous lesions, CHB, hepatic disease, and thrombocytopenia. IgG antibodies to Ro and/or La cross the placenta and participate in the development of the clinical manifestations. Mothers of babies with NLE are likely to develop collagen vascular diseases with time. Infants with NLE are at risk to develop other autoimmune diseases during childhood or adolescence.