Recurrent infectious diseases in human CD53 deficiency.
ABSTRACT We report a familiar syndrome of recurrent heterogeneous infectious diseases, caused by bacteria, fungi, and viruses, which has as its only detectable defect the lack of CD53 antigen expression in neutrophils. All other assays ruled out known causes of recurrent infectious diseases due to either leukocyte adhesion or phagocytosis defects. CD53 belongs to the transmembrane-4 superfamily of proteins, which are a novel group of membrane proteins implicated in growth regulation and cell motility and possibly cell adhesion. We postulate that defects in these membrane proteins can be clinically manifested as complex recurrent infections.
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ABSTRACT: Toxoplasma gondii can establish chronic infection and is characterized by the formation of tissue cysts in the brain. Although T. gondii can infect any kind of nucleated cells, macrophages and related mononuclear phagocytes are its preferred targets in vivo. Microglial cells are the resident macrophages in the central nervous system. It has been reported that CD37, a tetraspanin molecule, is expressed exclusively in the immune system; Dectin-1, an important pattern-recognition receptor, is expressed on the surface of murine primary microglia. The Dectin-1-CD37 association can affect Dectin-1-mediated IL-6 secretion. However, there is no report concerning the relationship among the expressions of Dectin-1, IL-6, and CD37 during T. gondii infection. In the present study, Kunming outbred mice were infected with Prugniaud (Pru), a type II strain of T. gondii by oral gavage, and BV-2 murine microglial cells were cocultured with RH tachyzoites of T. gondii. By H&E and immunohistochemical staining, the results showed that marked inflammation and a significantly increased activation of Iba1-positive microglial cells were observed in the brain tissues of mice infected with T. gondii Pru strain at 5 weeks postinfection (p.i.) in comparison of uninfected controls. Using quantitative real-time PCR detection, Dectin-1 messenger RNA (mRNA) expressions were significantly upregulated in both brains at 3 (P < 0.01), 5 (P < 0.01), 7 (P < 0.01), and 9 (P < 0.05) weeks p.i. and spleens at 3, 5, 7, and 9 weeks p.i. (P < 0.01). IL-6 expressions showed similar dynamic tendency as that of Dectin-1 in both the brains and spleens at the same times in comparison of uninfected controls; CD37 expressions were significantly increased in the brain tissues at all the times (P < 0.01) and no significant differences in the spleens at 3 weeks p.i. but significantly downregulated in the spleens at 5, 7, and 9 weeks p.i. (P < 0.01). In vitro study showed that compared with uninfected controls, the mRNA expressions of Dectin-1 at 2, 4, 8, and 10 h (P < 0.01); IL-6 at 8 and 10 h (P < 0.01); and CD37 at 4 (P < 0.05), 8 (P < 0.01), and 10 h (P < 0.01) were significantly upregulated in BV-2 murine microglial cells stimulated with RH tachyzoites of T. gondii. Our data suggested that the expression of Dectin-1 was positively correlated with that of IL-6 in toxoplasmic encephalitis (TE) mouse model; Dectin-1 interaction with tetraspanin CD37 regulated IL-6 expression in both the brain tissues of TE mouse model and in the T. gongdii-infected BV-2 murine microglial cells.Parasitology Research 05/2014; · 2.33 Impact Factor
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ABSTRACT: Gastrointestinal nematodes are one of the most serious causes of disease in domestic ruminants worldwide. There is considerable variation in resistance to gastrointestinal nematodes within and between sheep breeds, which appears to be due to underlying genetic diversity. Through selection of resistant animals, rapid genetic progress has been demonstrated in both research and commercial flocks. Recent advances in genome sequencing and genomic technologies provide new opportunities to understand the ovine host response to gastrointestinal nematodes at the molecular level, and to identify polymorphisms conferring nematode resistance.BMC Genomics 07/2014; 15(1):637. · 4.04 Impact Factor
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ABSTRACT: The plasma membrane of immune cells is a highly organized cell structure that is key to the initiation and regulation of innate and adaptive immune responses. It is well-established that immunoreceptors embedded in the plasma membrane have a nonrandom spatial distribution that is important for coupling to components of intracellular signaling cascades. In the last two decades, specialized membrane microdomains, including lipid rafts and TEMs, have been identified. These domains are preformed structures ("physical entities") that compartmentalize proteins, lipids, and signaling molecules into multimolecular assemblies. In APCs, different microdomains containing immunoreceptors (MHC proteins, PRRs, integrins, among others) have been reported that are imperative for efficient pathogen recognition, the formation of the immunological synapse, and subsequent T cell activation. In addition, recent work has demonstrated that tetraspanin microdomains and lipid rafts are involved in BCR signaling and B cell activation. Research into the molecular mechanisms underlying membrane domain formation is fundamental to a comprehensive understanding of membrane-proximal signaling and APC function. This review will also discuss the advances in the microscopy field for the visualization of the plasma membrane, as well as the recent progress in targeting microdomains as novel, therapeutic approach for infectious and malignant diseases.Journal of leukocyte biology 10/2013; · 4.99 Impact Factor
CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY,
Copyright ? 1997, American Society for Microbiology
Mar. 1997, p. 229–231Vol. 4, No. 2
Recurrent Infectious Diseases in Human CD53 Deficiency
FAUSTINO MOLLINEDO,1GUMERSINDO FONTA´N,2ISABEL BARASOAIN,3AND PEDRO A. LAZO4*
Instituto de Biologı ´a y Gene ´tica Molecular, Facultad de Medicina, CSIC-Universidad de Valladolid, 47005 Valladolid,1
Servicio de Immunologı ´a, Hospital Universitario La Paz, 28049 Madrid,2Centro de Investigaciones Biolo ´gicas (CSIC),
28006 Madrid,3and Unidad de Gene ´tica y Medicina Molecular (CSIC), Centro Nacional de Biologı ´a Fundamental,
Instituto de Salud Carlos III, 28220 Majadahonda,4Spain
Received 27 September 1996/Returned for modification 16 December 1996/Accepted 6 January 1997
We report a familiar syndrome of recurrent heterogeneous infectious diseases, caused by bacteria, fungi, and
viruses, which has as its only detectable defect the lack of CD53 antigen expression in neutrophils. All other
assays ruled out known causes of recurrent infectious diseases due to either leukocyte adhesion or phagocytosis
defects. CD53 belongs to the transmembrane-4 superfamily of proteins, which are a novel group of membrane
proteins implicated in growth regulation and cell motility and possibly cell adhesion. We postulate that defects
in these membrane proteins can be clinically manifested as complex recurrent infections.
Clinical syndromes characterized by recurrence of heteroge-
neous infectious diseases with several pathogenic agents are
frequently the result of two major types of deficiencies that
affect different aspects of leukocyte biology (2, 9). Members of
the first group of disorders are usually the result of defects in
leukocyte adhesion and cell motility properties, which are me-
diated by several proteins such as the integrins, CD11a,
CD11b, and CD18 (2). In the second group, the defects are in
the mechanisms of phagocyte killing related to oxidative prop-
erties, such as superoxide anion production in neutrophils,
causing recurrent-infection syndromes (9). This latter group
includes chronic granulomatous diseases (CGD) (9).
We have identified three members of a family, a 46-year-old
woman and her two sons, 18 and 20 years old, that have similar
clinical pictures, more severe in the mother, of heterogeneous
recurrent infectious diseases since early childhood affecting
several organs and caused by viruses, bacteria, and fungi.
These three patients have tuberculosis as a common infection.
All of them have to be frequently treated with antibiotics, in
addition to tuberculosis treatment, to have normal lives. They
usually do not feel well and get tired easily even in the absence
of an active infection.
The first patient is a woman, a daughter of first cousins. She
was diagnosed with pulmonary tuberculosis when she was 3
months old. Now her tuberculosis affects the intestine and
kidney, with lesions detectable by computerized axial tomog-
raphy scan; however, there is little lung damage. From early
infancy, she has had frequent upper respiratory tract infec-
tions. From 19 to 21 years of age, she suffered from chronic
diarrhea, with some bleeding. She has had recurrent esophagi-
tis and vaginitis caused by Candida albicans that have re-
sponded to antifungal drugs. Occasionally she has had crises of
arthritis or vasculitis that have responded very well to antibi-
otic treatment. There is calcification in her soft tissues, partic-
ularly near the backbone. There has been a loss of bone den-
sity. She suffers from a recurrent herpes infection. Her basal
temperature dropped to 35?C at age 40. She has mild allergies
to milk, pollen, and dust.
From 2 months to 11 years of age, the elder son had very
frequent intestinal and upper respiratory tract infections that
responded to antibiotic treatment. At 12 years of age, he had
salmonellosis and a mild crisis of meningitis that responded to
treatment; since then, his basal temperature has been 35?C. At
19 years of age, he was diagnosed with renal-intestinal tuber-
culosis. He continues to experience recurrent respiratory in-
Like his brother, the second son had frequent upper respi-
ratory tract infections until he was 7 years old; at that age, his
basal temperature dropped to 35?C. At 3 years of age, he had
a case of pneumonia that required hospitalization and re-
sponded to antibiotic treatment. At 13 years of age, intestinal
tuberculosis was diagnosed, with a new crisis at age 16. From
15 years of age, there have been recurrent new episodes of
upper respiratory tract infections. He has mild allergies to
milk, pollen, and dust. He has an enlarged spleen and liver. He
has experienced frequent episodes of infectious arthritis, af-
fecting the knee and ankle, which improves with antibiotics but
does not disappear. He has also had frequent viral infections,
including Epstein-Barr virus infections.
The general situations of these three patients improve con-
siderably when they receive chronic treatment with antibiotics.
However, these antibiotics have to be changed frequently due
to the appearance of resistance.
The heterogeneity and type of infectious agents suggested
that most of them were opportunistic infections or reactivation
of chronic silent infections in patients with an unidentified
Based on the suspicion of a likely immunodeficiency, we
determined several parameters to try to identify a possible
pathogenic factor for the diseases in these patients. The only
antigen we detected to be different in these three patients from
those in controls was CD53 (3, 14). We determined the CD53
surface antigen levels in neutrophils from several healthy in-
dividuals and these three patients. Two monoclonal antibodies
(MAb) against human CD53 antigen, MEM53 and HI29, rec-
ognizing different epitopes (12), were used. These antibodies
were obtained from Serotec (Oxford, United Kingdom) or
Pharmingen (San Diego, Calif.). Neutrophils were prepared by
standard procedures (20). The percentage of positive human
neutrophils isolated from healthy individuals (n ? 16) for
CD53 was over 85% in all cases. However, neutrophils from
these three patients were negative for this antigen, with ?5%
positive cells. The immunofluorescence flow cytometry pat-
terns are shown in Fig. 1. None of the patients appeared to
* Corresponding author. Mailing address: Centro Nacional de Bio-
logı ´a Fundamental, Instituto de Salud Carlos III, 28220 Majadahonda,
Spain. Phone: 34-1-509 7936. Fax: 34-1-509 7918. E-mail: plazozbi
have significant levels of CD53 antigen in neutrophils (Fig. 1B,
C, and D), whereas neutrophils from a healthy individual used
as a control showed high-level cell surface expression of this
antigen (Fig. 1A). Furthermore, in CD3-positive T cells, there
was no detectable CD53 antigen (not shown). In humans, all
mature cells of the lymphoid-myeloid lineage are positive for
CD53 antigen (3, 14). CD53 antigen is a member of the trans-
membrane-4 superfamily (also known as TM4SF or tetraspan
proteins), a novel group of glycoproteins whose physiological
function is unknown despite widespread cellular distribution
(23). However, this antigen has been shown to be involved in
cellular signaling in B (21, 22) and T and NK (4, 5) cells,
implicating both tyrosine kinases and protein kinase C (4, 21).
In human B cells and monocytes, cross-linking of CD53 anti-
gen triggers a respiratory burst (21). In mice, CD53 antigen
also appears to be implicated in thymic selection of immuno-
competent cells (17). In rat macrophages, CD53 antigen reg-
ulates the inducible nitric oxide system (6). Furthermore, the
CD53 antigen surface level appears to be downregulated after
neutrophil stimulation in a manner similar to the levels of
glycophorin (CD43) and hyaluronic acid receptor (CD44) (7,
19). This regulation suggested that CD53 antigen was impli-
cated in the modulation of cellular adhesion, although its nat-
ural ligand is still unknown. In this context, the clinical histo-
ries of these patients are similar in their heterogeneity to the
disease phenotypes reported for defects in cellular adhesion
To rule out other potential defects, we also determined the
cell surface expression of a number of leukocyte antigens in
these patients. Thus, different cell surface markers were ana-
lyzed by immunofluorescence flow cytometry using distinct
MAb in a Becton Dickinson FACStar Plus flow cytometer.
Cellular staining and analyses of different cell subpopulations
were performed by standard techniques. All other MAb used
in this work were from Becton Dickinson (San Jose ´, Calif.),
Immunotech (Westbrook, Maine), or Pharmingen. The spe-
cific reactivities of MAb markers for different cell populations
and subpopulations were within normality levels and similar to
those from control individuals. These other markers included
CD2, CD3, CD4, CD5, CD7, CD8, CD11a, CD11b, CD11c,
CD14, CD16, CD18, CD19, CD20, CD21, CD25, CD56, CD57,
Leu 4, RO, RA, T-cell receptor ??, T-cell receptor ??, HLA-
DR, DQ, and DP. The immunoglobulin levels were within the
lower limits of normal values (Table 1). We expected the
immunoglobulin G (IgG) values to be significantly higher be-
cause of chronic infections. Their mitogenic responses to en-
terotoxins A and C1, interleukin-2 (IL-2), MAb OKT3, and
several lectins, including concanavalin A, phytohemagglutinin,
and pokeweed, were also normal.
NK cell cytolytic activity was tested by using different ratios
of effector to target cells (ranging from 100 to 12.5); in these
three patients, the values were in the middle of the normal
In the T-cell population, CD53-positive cells represented
?1% of cells, regardless of the type, which is in contrast to the
situation in a healthy individual, where all populations are
positive (3). This observation suggested that the CD53 defi-
ciency was a general phenomenon and was not restricted to
neutrophils. The CD4?/CD8?lymphocyte ratios for two pa-
tients were within the lower limit (Table 1).
The production of several cytokines after intravenous stim-
ulation with 3 ng of endotoxin per kg was determined during a
24-h period. In these three patients, the levels of tumor necro-
sis factor alpha (TNF-?), small TNF-? receptor, granulocyte-
macrophage colony-stimulating factor, IL-8, IL-1?, IL-6, IL-4,
gamma interferon, and lactoferrin and changes in temperature
were within normal control variation.
Recurrent infections are also part of the clinical phenotype
of CGD (9). Therefore, we tested for neutrophil functional
properties affected in CGD. However, all markers for CGD
were negative. Neutrophil cellular immunity appeared to be
normal, as assessed by several functional studies of phagocyte
activity (9), such as Escherichia coli and C. albicans phagocy-
tosis, and biological mechanisms of cell toxicity, such as gen-
eration of superoxide anion and the Nitro Blue Tetrazolium
FIG. 1. Immunofluorescence flow cytometry of CD53 antigen cell surface
levels in human neutrophils from a control individual (A), the affected mother
(B), the elder son (C), and the younger son (D). Cells were analyzed with MAb
MEM53 (anti-human CD53) (solid lines). The determination of CD11b antigen
with MAb Bear1 was used as the positive control (broken lines). The background
and negative control were determined with P3X63 myeloma supernatant (dotted
TABLE 1. Laboratory parameters
Mother First son
IgG level (mg/dl)
IgA level (mg/dl)
IgM level (mg/dl)
IgE level (IU/ml)
C3 level (mg/dl)
C4 level (mg/dl)
1,250 ? 300
210 ? 50
125 ? 50
aIn the cases of IgG, IgA, and IgM levels, data are two determinations
performed at a 2-year interval.
230NOTESCLIN. DIAGN. LAB. IMMUNOL.
reduction. The results of all these tests were within normality
levels for all three patients, ruling out a CGD. We performed
additional assays to determine neutrophil responses to stimu-
lation with phorbol esters, TNF-?, and FMLP, a chemotactic
peptide. In this regard, we found in these patients CD11b cell
surface upregulation similar to that of controls after neutrophil
stimulation with the stimuli listed above (data not shown). This
CD11b upregulation is due to the rapid mobilization of sec-
ondary and tertiary granules to the membrane in human neu-
trophils (16). However, CD53 was not upregulated in controls
or patients upon neutrophil activation by either phorbol esters,
such as phorbol myristate acetate, or FMLP (not shown).
The levels of several complement proteins, such as C3 and
C4, were within the lower limits of normal values (Table 1).
The levels of C5a were similar to those in controls.
The inheritance pattern of the clinical phenotype appears to
be autosomal dominant, consistent with localization of the
human CD53 gene on chromosome region 1p13.3 (10), which
is different from the location where other similar syndromes
have been mapped (2, 9). The parents of the mother are first
cousins and were not available for this study. However, this
genetic defect either may be present in the CD53 gene itself (in
that case, the phenotype is dominant over the normal allele) or
is due to a regulatory problem, such as alteration of a regula-
tory gene and therefore there is no expression of the CD53
gene. This issue will be resolved when molecular characteriza-
tion of the defect becomes feasible.
Recent experiments on the role that some transmembrane-4
superfamily proteins play in the cancer phenotype suggest an
explanation for the pathophysiology of these reported cases. In
different cancers, CD9/MRP1 and CD82/KAI1 proteins ap-
pear to function as brakes of cell motility (8, 15). Thus, low
levels of these antigens facilitate the spread of the tumor and
metastasis formation (1, 8, 11, 13, 15, 18). In the present
clinical cases of low levels of CD53 antigen, if its effect on cell
motility is to act as a brake, one would expect the activated cell
not to stop at the location of infection, although the functional
parameters are normal, thus preventing the execution of its
normal defensive function at the site of infection.
We show here that CD53 deficiency might be a pathogenic
factor in some immunodeficiency syndromes of recurrent mul-
tiple infections with known infectious agents but unknown
pathophysiology. To our knowledge, we report here data for
the first clinical syndrome in which the CD53 antigen level is
altered; no previous data relating an alteration in CD53 ex-
pression to clinical conditions similar to those in these patients
are available. Therefore, this and perhaps some other TM4SF
protein(s) should represent a novel underlying, though prob-
ably rare, cause of these defects.
This work was supported by Direccio ´n General de Ciencia y Tec-
nologı ´a grant PB95/0713 (to F.M.), Comisio ´n Interministerial de Cien-
cia y Tecnologı ´a grant SAF94/0059 (to P.A.L.), and Fondo de Inves-
tigacio ´n Sanitaria grants FIS95/0413 (to P.A.L.) and FIS96/1434 (to
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VOL. 4, 1997NOTES 231