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. Author manuscript; available in PMC: 2014 Dec 14.
Published in final edited form as: Int J Rheum Dis. 2013 Dec 14;16(6):674–680. doi: 10.1111/1756-185X.12254

Prolidase deficiency breaks tolerance to lupus-associated antigens

Anil Dsouza 1, Biji T Kurien 1, Benjamin F Bruner 1, Timothy Gross 1, Judith A James 1,2, Ira N Targoff 1,2, Jacen S Maier-Moore 1,2, Isaac TW Harley 4, Heng Wang 3, R Hal Scofield 1,2,3
PMCID: PMC4030668  NIHMSID: NIHMS545214  PMID: 24330273

Abstract

Background

Prolidase deficiency is a rare autosomal recessive disease in which one of the last steps of collagen metabolism, cleavage of proline-containing dipeptides, is impaired. Only about 93 patients have been reported with about 10% also having systemic lupus erythematosus (SLE).

Methods

We studied a large extended Amish pedigree with four prolidase deficiency patients and three heterozygous individuals for lupus-associated autoimmunity. Eight unaffected Amish children served as normal controls. Prolidase genetics and enzyme activity were confirmed. Antinuclear antibodies (ANA) were determined using indirect immunofluorescence and antibodies against extractable nuclear antigens were determined by various methods, including double immunodiffusion, immunoprecipitation and multiplex bead assay. Serum C1q levels were determined by enzyme-linked immunosorbent assay.

Results

Two of the four homozygous prolidase deficiency subjects had a positive ANA. One had anti-double-stranded DNA, while another had precipitating anti-Ro. By the simultaneous microbead assay, three of the four had anti-Sm and anti-chromatin. One of the three heterozygous subjects had a positive ANA and immunoprecipitation of a 75 000 molecular weight protein. The unaffected controls had normal prolidase activity and were negative for autoantibodies.

Conclusions

Prolidase deficiency may be associated with the loss of immune tolerance to lupus-associated autoantigens even without clinical SLE.

Keywords: prolidase deficiency, systemic lupus erythematosus, autoantibodies

Introduction

Prolidase deficiency (OMIM ID#170100) was first described in 1968,1 and is a rare autosomal recessive inborn error of metabolism. Only about 93 patients2–20 have been described, all characterized by an absence of prolidase activity, an enzyme that cleaves proline-containing dipeptides as one of the final steps of collagen metabolism. Diagnosis is typically based on the presence of proline-containing dipeptides in the urine. Most patients have been diagnosed in childhood, with a few receiving a diagnosis as adults.10

Symptoms and signs of the disease are highly variable,9–12,18 but skin involvement is a commonly reported feature. Chronic lower extremity skin ulceration is characteristic, while other reported skin manifestations are telangiectasia, photosensitivity, edema and an eczema-like skin rash. Frontal bossing, low hairline and saddle nose deformity combine to make up characteristic facies. Mild intellectual disability has been reported in a few patients, but is far from a universal finding. Several individuals have been described with complete prolidase deficiency in the absence of clinical signs or symptoms,13,14,20 mostly by enzyme activity or urinary amino acid determination in siblings of known homozygous deficient patients.

Immune abnormalities as well as frequent infection have been described in prolidase deficiency; however, a specific immune defect responsible for the common finding of recurrent respiratory tract infections has not been identified.21 Elevated immunoglobin levels are reported in several patients.9,15–17 Abnormal chemotaxis of neutrophils has been reported in prolidase-deficient children and could be related to the increased rate of infections.8 A deficiency of C1q, which contains about 25% proline (similar to collagen) has been hypothesized as a cause of infections.22

Systemic lupus erythematosus (SLE) is a clinically, serologically and genetically complicated disease.23 Five prolidase-deficient patients have had SLE,8,17,21 while two others had a lupus-like illness with photosensitivity, antinuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA) and anti-Sm antibodies.24 The onset of lupus has been mostly in childhood among these patients who also have prolidase deficiency. A mechanism by which prolidase deficiency might predispose to lupus has not been found. No other illnesses have been associated with prolidase deficiency.

We undertook the present study to determine the presence of lupus-associated autoantibodies in the serum of prolidase-deficient patients as well as their heterozygous-deficient relatives. We studied three interrelated nuclear families containing four prolidase deficiency patients.

Methods

Subjects

Prolidase patients and their families were recruited after being identified clinically by one of us (HW). After written informed consent and age-appropriate assent of minors were obtained, blood was collected by routine phlebotomy under protocols approved by the Institutional Review Boards of the Oklahoma Medical Research Foundation (OMRF) and the University of Oklahoma Health Sciences Center (the protocol conforms to the provisions of the World Medical Association’s Declaration of Helsinki and patient anonymity has been preserved). All subjects were members of the same Amish community.

Serology

Serological studies were performed at the OMRF Clinical Immunology Laboratory, a Clinical Laboratory Improvement Amendments approved facility. ANA, including titers, were determined by indirect imunofluorescence using a HEp-2 substrate.25 Anti-dsDNA antibodies were determined by Crithidia lucilliae kinetoplast immunofluorescence method.26 Antibodies to extractable nuclear antigens (ENA) were determined by Ouchterlony agar gel immunodiffusion.27 Immunoprecipitation was performed as we have previously described.28

Multiplex serological studies

Autoantibody analysis was also performed using the Bio-Rad BioPlex 2200 ANA (Bio-Rad, Hercules, CA, USA), following the recommendations of the manufacturer as we have previously reported.29 This detects antibodies against any of the following antigens: 60 kD Ro, 52 kD Ro, La, SmRNP complex, Sm, RNP 68, RNP A, centromere B, Scl-70 (topoisomerase 1), Jo-1, chromatin, dsDNA, and ribosomal P. The BioPlex 2200 ANA screen reports a semi-quantitative value from 0 to 8, termed the antibody index (AI), for each autoantibody. The positive cut-off for each assay is established by the manufacturer and is equal to 1.0 for each assay, except for anti-dsDNA, which is a quantitative assay reporting IU/mL with10 IU/mL as the upper limit of normal.

Prolidase assay

Prolidase enzyme activity was measured as we have previously reported.30,31

Genetics of prolidase

Mutations in the prolidase gene were determined as we have previously reported.31

Complement C1q

We determined serum C1q levels as previously reported using a sandwich enzyme-linked immunosorbant assay (ELISA).32

Results

There were four prolidase-deficient patients available for study (subjects VIII-6, IX-2, IX-3 and IX-5 in Fig. 1) along with four family members without prolidase deficiency. Two of these family members were obligatory heterozygotes, that is, parents of prolidase-deficiency patients (subjects VII-1 and VII-2 in Fig. 1). A grandparent of the prolidase-deficient patients was also heterozygous deficient (subject VII-6 in Fig. 1). Finally, eight unaffected Amish children were studied. Each of the patients was shown to be homozygous for a single base pair change in the prolidase gene, resulting in a premature stop codon31 and determined to have absent enzyme activity.30 Subjects VII-1, VII-2 and VII-6 were heterozygous for the stop codon mutation and had enzyme activity about half of normal.30,31 Meanwhile, the unaffected controls had normal enzyme activity and no mutation of the prolidase gene.

Fig. 1.

Fig. 1

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Family structure of the prolidase-deficient subjects.

The demographics of the prolidase-deficient subjects are given in Table 1. The diagnosis of prolidase deficiency was in childhood, and very early in several subjects who were screened for the disease based on having an affected older sibling. The age at which serum was drawn for the present study ranged from 6 days to 6 years of age (Table 1).

Table 1.

Demographics and autoantibody data in the prolidase-deficient subjects and their heterozygous relatives.

Subject Genetics ANA Anti-ENA Anti-dsDNA Immunoprecipitation Microbead
VIII-6 Homozygous Negative Negative Negative UIB At 75 kd Data from test not readable
IX-2 Homozygous 1:360, NS Negative Negative Negative Anti-Sm 2.9, anti-chr 5
anti-Sm/RNP 1
IX-3 Homozygous 1:360, NS/C Anti-Ro Positive Negative Anti-Sm 1.1, anti-chr 1.5
IX-5 Homozygous Negative Negative Negative Negative Anti-Sm 3.8, anti-chr 2.3
VII-6 Heterozygous Negative ND Negative UIB At 75 kd Negative
VII-1 Heterozygous Negative ND Negative Negative Negative
VII-2 Heterozygous 1:120, NS/C ND Negative Negative Negative
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ANA determined by indirect immunofluorescence. ANA, antinuclear antibodies; Anti-ENA, extractable nuclear antigens; NS, nuclear speckled ANA pattern of fluorescence; C, cytoplasmic fluorescence. Anti-ENA determined by double immunodiffusion. UIB, unidentified precipitated protein. Anti-dsDNA determined by Crithidia luciliae assay with dilution ≥ 10 considered positive. Microbead assay gives a semi-quantitative result of from 0 to 8 with ≥ 0.2 considered positive. Anti-Sm, anti-Smith; anti-chr, anti-chromatin; ND, not determined.

We studied lupus-associated autoantibodies in the prolidase-deficient subjects, their heterozygous family members and the controls by routine clinical methods. Of the four with prolidase deficiency, we found that two had a positive ANA. The patterns found included nuclear-speckled as well as cytoplasmic. One prolidase-deficient subject had anti-Ro (or Sjögren’s syndrome antigen A [SSA]) but no other anti-ENA (anti-ribonucleoprotein [anti-RNP], anti-Sm, anti-La [or SSB], anti-Ku, anti-Jo1) were present by immunodiffusion (Table 1). This same prolidase-deficient subject also had low-level positive anti-dsDNA on the Crithidia assay as well as an unidentified line in immunodiffusion.

Anti-ENA positivity by double immunodiffusion requires a high titer of high-affinity antibodies and is, therefore, highly specific but poorly sensitive, especially for low levels of autoantibodies. In order to determine whether there were low levels of lupus-associated autoantibodies we tested the serum samples from prolidase-deficient subjects using a bead-based assay. This assay simultaneously measures antibody binding to 15 different autoantigens. We found that the three tested prolidase-deficient sera were positive for anti-Sm and anti-chromatin by this assay (Table 1).

We studied three subjects who were heterozygous for the mutation in the prolidase gene. One of these had a low-positive ANA and another had an unidentified band in protein immunoprecipitation. Immunoprecipitation of a band of similar mobility (~75 000 molecular weight) was also observed for one of the prolidase-deficient patients. The other heterozygous subject had negative results on ANA, immunoprecipitation and BioPlex 2200 testing (see Table 1).

The eight normal controls, who were also members of the same Amish community, were ANA, anti-dsDNA and anti-ENA negative as well on the bead assay.

One potential explanation for an association of SLE with prolidase deficiency is a deficiency of C1q among patients with prolidase deficiency. C1q has a collagen-like domain and is therefore proline rich.33 So, loss of proline-containing dipeptides could conceivably lead to C1q deficiency among those with prolidase deficiency as these patients have difficulty with collagen synthesis. However, we determined C1q levels in individuals with prolidase deficiency and found these were normal (Fig. 2).

Fig. 2.

Fig. 2

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Serum C1q levels in prolidase-deficient patients and their heterozygous relatives.

Discussion

Generally, SLE is a genetically complex human illness. While up to 50 genetic intervals have been shown to contain susceptibility genes for the disease in genome-wide association studies, this represents only a fraction of the heretibility of SLE.34 However, some patients with SLE carry mutations of genes encoding the early complement components such as C2, C4 or C1q,22,35–37 and have a monogenic form of SLE. Greater than 90% of individuals with complete deficiency of C1q have SLE, while 75% of individuals with complete deficiency of C4 have SLE. A smaller percentage, 10%, of individuals with complete C2 deficiency, have SLE.22 However, only 1% of families with two or more SLE patients have complement deficiency.38

Prolidase deficiency is a rare autosomal recessive disease with complete absence of prolidase enzyme activity. In addition to a variety of clinical features described in these patients, about 10% have had SLE or a lupus-like illness. The SLE manifestations in these patients as well as demographic data extracted from existing literature are given in Table 2. All but one had an onset of SLE or a lupus-like illness in childhood. Five of the eight met the usual criteria for classification as SLE (Table 2).39,40 Thus, prolidase deficiency is another monogenic form of SLE in which about 10% of patients with complete deficiency have SLE.

Table 2.

Previously reported prolidase-deficient patients with systemic lupus erythematosus or positive lupus-associated serology.

Reference Age/sex Ethnicity Clinical manifestations Serology Meets ACR criteria
Bissonette, 1993 16/girl NS Photosensitive rash, renal, arthritis, Raynaud’s ANA, RF Yes
Falik-Zaccal, 2010 10/girl Druze AIHA, thrombocytopenia, neutropenia, splenomagaly anti-dsDNA ACL, ANA No, 3 only
8/girl Arabic Mouth ulcers, renal, AIHA, neurologic, splenomegaly anti-dsDNA ANA, low C3/C4 Yes
Di Rocco, 2007 4/boy Italian ?Vasculitis, splenomegaly Anti-dsDNA ANA, anti-Ro, Low C3/C4 No, 2 only
Klar, 2010 4/girl Arabic Photosensitive rash, Raynaud’s, splenomegaly anti-dsDNA ANA, anti-Sm anti-RNP, low C3 No, 3 only
12/boy Arabic No lupus clinical feature splenomeagaly Anti-dsDNA, ANA, low C3 No, 2 only
Shrinath, 1997 7/boy Indian Arthritis, mouth ulcers, neutropenia, pericarditis, thrombocytopenia, renal malar rash anti-dsDNA, ANA Yes
5/girl Indian Neutropenia, mouth ulcers thrombocytopenia malar rash, AIHA ANA, ACL, pANCA Yes
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Age at diagnosis of SLE or lupus-like illness is given. ACR, American College of Rheumatology; NS, not stated; ANA, antinuclear antibodies; RF, rheumatoid factor; anti-ds DNA, anti-double-stranded DNA; ACL, anticardiolipin; Anti-Sm, anti-Smith; anti-RNP, anti-ribonucleoprotein; AIHA, autoimmune hemolytic anemia; pANCA, perinuclear anti-neutrophil cytoplasmic antigen

One child reported by Klar et al. had a lupus-like illness but met only three (four are required for research classification) of the revised 1982 American College of Rheumatology SLE classification criteria.39,40 The other subject reported by Klar and colleagues24 had no clinical feature of SLE but had both positive ANA and anti-dsDNA. Thus, this subject met two of the 11 criteria.39,40 Another patient also had only the serological features of ANA, anti-dsDNA and anti-Ro.17 Thus, these prolidase patients are similar to those reported herein. There were autoantibodies but no clinical disease consistent with SLE. In a study of 28 patients with incomplete lupus (that is, less than four criteria), 57% went on to develop full SLE, fulfilling four or greater criteria in a median time of 5.3 years. The presence of malar rash or anti-cardiolipin was a predictor of progression but anti-dsDNA was not.41 However, longitudinal follow-up of the ‘partial’ SLE patients is brief in these reports. Thus, some of these prolidase-deficient and incomplete lupus patients may go on to develop SLE as defined by the classification criteria.39,40

We found that three prolidase-deficient patients have not only positive ANA but also have low levels of anti-Sm. While ANA are generally non-specific for SLE, anti-Sm is highly specific for SLE.42 Our patients and the previously reported ones with either SLE or incomplete lupus demonstrate that prolidase deficiency can result in a loss of tolerance to lupus-associated autoantigens. Some prolidase-deficient individuals only have antibodies against the Sm antigens of the spliceosome, the 60 kD Ro antigen of the Ro-hYRNA complex, chromatin, or native DNA (Tables 1 and 2). Other prolidase-deficient individuals develop an incomplete lupus with serological positivity and some clinical features of the disease (Table 2). Finally, about 10% of all prolidase-deficient patients ever reported have overt, full-blown SLE (Table 2). So, while the manifestations of lupus-associated autoimmunity vary in prolidase deficiency, in our cohort, one of the largest ever assembled, lupus-associated autoimmunity is universal.

The mechanism by which prolidase deficiency predisposes to SLE is unknown. However, there are several possibilities. As stated earlier, C1q is proline-rich and its synthesis might be affected by free proline deficiency resulting from a lack of prolidase activity. Genetic deficiency of C1q is known to cause SLE, probably through a mechanism that involves impaired apoptosis.22,35–37 However, we found normal C1q levels among our four prolidase-deficient subjects. Thus, this mechanism is unlikely. Apoptosis may be affected by a lack of free proline through another mechanism. Proline oxidase is a proapoptotic enzyme located on the mitochondrial inner membrane and converts proline to pyrroline 5-carboxylate.43 This action transfers electrons into the mitochondrial electron transport system. Proline oxidase is induced by p5344 and mediates apoptosis, possibly through oxygen radical generation.45 Clearly, defects in apoptosis are important in the pathogenesis of SLE,46 and a lack of free proline, which is produced by prolidase, may impair apoptosis mediated through proline oxidase.

Chemotaxis has been found abnormal in a few prolidase-deficient patients.8 The tripeptide prolyl-glycyl-proline (PGP), which is produced from the metabolism of collagen, is chemotactic for neutrophils via binding of the chemokine receptors CXCR1 and CXCR2.47 An N-terminal proline is cleaved from PGP by leukotriene A4-hydrolase, producing glycine-proline dipeptides and regulating inflammation.48 These remaining proline-containing dipeptides should be metabolized by prolidase. Lack of enzymatic degradation in prolidase deficiency may be the mechanism underlying the abnormal chemotaxis found among prolidase-deficient subjects. This pathway has not been well characterized in either prolidase deficiency or SLE. However, the recent appreciation that neutrophils recruited to sites of inflammation provide an abundant source of autoantigenic material, which correlates with SLE disease activity (http://www.ncbi.nlm.nih.gov/pubmed/22617827), suggests another potential mechanism leading to autoimmunity in prolidase deficiency. Impaired resolution of neutrophilic inflammation resulting from prolidase deficiency could result in increased exposure to autoantigenic material in the setting of acute inflammation where normal tolerogenic signals are absent, resulting in autoimmunity.

We found that subjects with prolidase deficiency frequently have autoantibodies binding lupus-associated autoantigens. Further, a significant percentage of prolidase patients develop SLE, or an SLE-like illness. Low C1q is not found in prolidase-deficient subjects and thus, is not a viable candidate to explain the mechanism of SLE autoimmunity in prolidase deficiency. There is specific association of antibodies to Sm in homozygous prolidase-deficient patients and not in heterozygous as well as control patients. Moreover, lupus is itself a rare disease and prolidase deficiency is a much rarer disease. Therefore, we believe that the association of anti-Sm results with prolidase deficiency are more likely to be real rather than by chance. Determining the pathogenic mechanism by which these two diseases are connected may shed light on the pathogenesis of both.

Acknowledgments

We greatly appreciate the willingness of the prolidase-deficient patients and their families to participate in this study. We also greatly appreciate the technical assistance provided by Skyler P. Dillon. The study was funded in part by NIH grant AR4820 (RHS) and The Elisabeth Severance Prentiss Foundation, The Reinberger Foundation, the Leonard Krieger Fund of the Cleveland Foundation (L2009-0078) (HW).

Footnotes

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

Anil Dsouza formulated scientific plan, performed experiments.

Biji T. Kurien formulated scientific plan, edited manuscript, performed experiments.

Benjamin F. Bruner performed experiments.

Timothy Gross performed experiments.

Judith A James formulated scientific plan.

Ira N. Targoff formulated scientific plan.

Jacen S. Maier-Moore formulated scientific plan, edited manuscript.

Isaac T.W. Harley formulated scientific plan, edited manuscript.

Heng Wang recruited patients, formulated scientific plan, edited manuscript.

R. Hal Scofield formulated scientific plan, wrote the manuscript.

All authors approved final version of manuscript.

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