The role of human endogenous retroviruses in the pathogenesis of autoimmune diseases.
ABSTRACT This paper presents a new, recently formulated theory, which concerns the etiopathological process of autoimmune diseases. This theory takes into account the existence in the human genome, since approximately 40 million years, of so-called human endogenous retroviruses (HERVs), which are transmitted to descendants "vertically" by the germ cells. It was recently established that these generally silent sequences perform some physiological roles, but occasionally become active and influence the development of some chronic diseases like diabetes, some neoplasms, chronic diseases of the nervous system (eg, sclerosis multiplex), schizophrenia and autoimmune diseases. We present a short synopsis of immunological processes involved in the pathogenesis of autoimmune diseases, such as molecular mimicry, epitope spreading and activation of the superantigen. We then focus on experimental findings related to systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and some diseases of hepar and otorhinal tissues. We conclude the outline of this new model of the development of chronic diseases and indicate the conclusions important for the teaching of the basis of pathology.
- [show abstract] [hide abstract]
ABSTRACT: It has long been discussed whether endogenous retroviruses (ERVs) are involved in the pathogenesis of autoimmune diseases. Among various human endogenous retroviruses (HERVs), we have focused on HERV-R. To investigate the biological roles of HERV-R, we earlier established transgenic rats carrying the full sequence of the viral genome. In these HERV-R rats, however, no disease occurred. Another trigger that induces autoimmunity may be essential for the recognition of HERV-R products by the immune system. Thus, in this study, we mated HERV-R rats with env-pX rats (transgenic rats carrying the env-pX gene of human T cell leukemia virus type I) that develop autoimmune diseases, and generated double transgenic (DTG) rats. In DTG rats, autoimmune diseases occurred similarly in env-pX rats. Interestingly, deposition of rat IgM but not IgG was observed on the glomerular endothelial cells. Such IgM deposition was never seen in the parental HERV-R or env-pX rats. We considered that in situ formation of immune complexes consisted of the HERV-R env glycoprotein and anti-HERV-R env IgM antibodies (Abs) in DTG rats, according to the following evidence: (1) No dense deposit, representing deposition of circulating immune complexes, was seen on glomerular endothelial cells. (2) IgM Abs reactive with HERV-R env glycoprotein were generated in the serum. (3) HERV-R env glycoprotein was expressed in the kidney, specifically on glomerular endothelial cells. (4) IgM deposition was partly colocalized with the HERV-R env glycoprotein on the glomeruli. These findings strongly suggest that the HERV-R env glycoprotein is recognized as an autoantigen in the host with autoimmune diseases.AIDS research and human retroviruses 09/2009; 25(9):889-96. · 2.18 Impact Factor
Article: Malignancy and autoimmunity.[show abstract] [hide abstract]
ABSTRACT: The association of cancer with autoimmune disease has been under investigation for several years. Reports have appeared suggesting increased cancer risk in autoimmune rheumatic diseases. Evidence has been accumulating recently in rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, and scleroderma/systemic sclerosis. This review focuses on recent publications regarding risk of cancer in these conditions. Despite a lack of a strong association between rheumatoid arthritis and cancer overall, studies show an increased risk for the development of lymphoma in rheumatoid arthritis. There are data suggesting an increased risk for rheumatoid arthritis patients regarding lung cancer. In Sjogren's syndrome-related malignancies, most publications in the past year relate to non-Hodgkin's lymphomas, and suggest possible mechanisms driving the association. Data substantiate an increased risk of certain cancers in systemic lupus erythematosus; the risk appears to be most heightened for lymphoma. A recent cohort study examined cancer risk in scleroderma; the estimates were lower than previous studies had suggested, and the confidence intervals relatively imprecise, making a definitive conclusion difficult. There have been several papers published related to cancer in the rheumatic diseases, particularly inflammatory arthritis, Sjogren's syndrome, systemic lupus erythematosus, and scleroderma/systemic sclerosis. Continuing interest in the association between autoimmune rheumatic diseases and malignancy is likely, given the potential impact in terms of understanding both rheumatic diseases and cancer.Current Opinion in Rheumatology 04/2006; 18(2):129-34. · 5.19 Impact Factor
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ABSTRACT: The complete sequence of XA34 was identified from a 107 kb genomic clone originating from the human chromosome 7q31.1-q31.3. The 7.1 kb human endogenous retrovirus (HERV) contains LTR's, gag, pol and env, and a pol sequence which is identical to the 2.3 kb XA34 cDNA clone which we previously isolated from a human glioma cDNA library (Widegren et al., 1996). The HERV is located in a reversed orientation within an intron-sequence of a gene similar to mouse adseverin(D5). The gag and protease regions are intact. However, the pol and env regions are truncated by a deletion which removes the C-terminal end of the integrase and the complete surface protein. The HERV sequence is bordered by a five base-pair direct repeat and has the TG…CA structure. Over the complete HERV genome, XA34 is very similar to members of the HERV-F family and shares the same primer binding site which is homologous to phenylalanine (F) tRNA. Therefore, XA34 is termed HERV-F(XA34). HERV-F(XA34) has an open reading frame (ORF) of 1000 bp in the gag region which starts with Met-Gly in a favorable context and stops in the capsid protein. A strong mRNA expression of HERV-F(XA34) is demonstrated in placental tissue, mainly residing in two transcripts of approximately 7.5 and 8.5–9 kb respectively. Analyses of expressed sequence tags (ESTs) have identified the expression of HERV-F(XA34) sequences in placental tissue, fetal liver/spleen, olfactory epithelium and in an epithelial skin tumor. EST analysis has also identified splice variants of HERV-F(XA34), in which the gag, pol and most of the env regions are spliced out. These splice variants contain a short ORF encoded in the region from the C-terminal portion of env to the 3′-LTR. In addition, ESTs identical to HERV-Fb have been identified in retinal, fetal liver/spleen and brain tissue as well as Jurkat cells. The analyses indicate that the 5′-LTR of HERV-Fb may function as an alternative poly A site of a Krüppel related zinc finger gene (ZNF195).Gene 11/1999; · 2.20 Impact Factor
The role of human endogenous retroviruses
in the pathogenesis of autoimmune diseases
Andrzej Brodziak, Ewa Ziółko, Małgorzata Muc-Wierzgoń,
Ewa Nowakowska-Zajdel, Teresa Kokot, Katarzyna Klakla
Department of Internal Diseases, Faculty of Public Health, Medical University of Silesia, Bytom, Poland
Source of support: Self financing
This paper presents a new, recently formulated theory, which concerns the etiopathological pro-
cess of autoimmune diseases. This theory takes into account the existence in the human genome,
since approximately 40 million years, of so-called human endogenous retroviruses (HERVs), which
are transmitted to descendants “vertically” by the germ cells. It was recently established that these
generally silent sequences perform some physiological roles, but occasionally become active and
influence the development of some chronic diseases like diabetes, some neoplasms, chronic dis-
eases of the nervous system (eg, sclerosis multiplex), schizophrenia and autoimmune diseases. We
present a short synopsis of immunological processes involved in the pathogenesis of autoimmune
diseases, such as molecular mimicry, epitope spreading and activation of the superantigen. We
then focus on experimental findings related to systemic lupus erythematosus, rheumatoid arthri-
tis, Sjögren’s syndrome and some diseases of hepar and otorhinal tissues. We conclude the outline
of this new model of the development of chronic diseases and indicate the conclusions important
for the teaching of the basis of pathology.
key words:? autoimmune?diseases?•?systemic?lupus?erythematosus?•?human?endogenous?retroviruses?•?
?Author’s?address: Andrzej Brodziak, Department of Internal Diseases, Faculty of Public Health, Medical University of Silesia,
Zeromskiego 7 St., 41-902 Bytom, Poland, e-mail: firstname.lastname@example.org
© Med Sci Monit, 2012; 18(6): RA80-88
Current Contents/Clinical Medicine • IF(2010)=1.699 • Index Medicus/MEDLINE • EMBASE/Excerpta Medica • Chemical Abstracts • Index Copernicus
In recent years evidence has accumulated that supports
a significant relationship between the so-called Human
Endogenous Retroviruses (HERV) and the development
of different autoimmune diseases [1–4], which suggests
we need to change our understanding of the pathogene-
sis of these chronic diseases, including diabetes, some neo-
plasms and chronic diseases of the nervous system like scle-
rosis multiplex and even schizophrenia [5–10].
In this article we present a new, unusual model of the de-
velopment of chronic diseases, especially the most common
Until recently, a simple, teaching model of pathogenesis
recognized diseases caused by infectious agents, by chemi-
cal, physical and mechanical effects of the external environ-
ment, and pathogenesis involving genetic factors.
Some diseases are determined genetically by changes at the
level of chromosomes (eg, Down syndrome), or by exactly
known “point” changes in the structure of specific genes,
such as in the case of hemophilia. Many diseases are un-
doubtedly genetically determined, as evidenced by epide-
miological studies carried out on homozygous twins; how-
ever, the pathogenetic mechanisms are complex and, until
The statistical comparisons concerning the incidence of some
diseases, made on groups of homozygotic twins, show that
schizophrenia, manic-depressive illness and multiple sclerosis
are genetically caused diseases. If one of the so-called ‘mono-
zygotic twins’ has schizophrenia or manic-depressive illness,
there is a probability of about 50% that the second twin will
also have the same disease. The analogous figure for multiple
sclerosis is 30% and for type 1 diabetes approximately 40%.
In discussing the pathogenesis of these diseases, it is usual-
ly understood that the onset of these diseases is affected by
changes in many genes, although it was not possible to dem-
onstrate precisely the regions of the genome containing the
errors influencing these diseases. People studying genetics as
a basic field important for the understanding of pathogen-
ic mechanisms have long been acquainted with facts relat-
ed to some types of repeated nucleotide sequences, present
in the human genome, which are not genes  (Figure 1).
The human genome includes about 3 billion base pairs, or-
ganized into 23 pairs of chromosomes. Only about 5% of
the DNA polynucleotides consist of structural genes, cod-
ing for the synthesis of certain proteins. According to the
authors of the “Human Genome Project” and Craig Venter,
who also sequenced the whole human genome, there are
only about 30 000 to 50 000 structural genes.
Non-coding polynucleotides constitute approximately 80%
of the total genome. One group of these is called the pseu-
dogenes, which are damaged, non-acting versions of known
genes. Textbooks of genetics also distinguish between so-
called “moderately and frequently repeated sequences”
and “sequences unique or in small number of copies” .
Among the repeated sequences, distinction is made between
“short interspersed nuclear elements” (SINE) and the “long
interspersed nuclear elements” (LINE).
The most familiar SINE element is the “Alu sequence”,
which is a “family” of polynucleotides (sequences quite
similar), with an average length of 250 bp; approximately
700 000 copies are present in the genome. LINE elements
are longer. For example, the well-known L1 LINE element
has a length of 6500 bp and 60 000 copies are present in
the genome. Classical genetics textbooks emphasize that
LINE elements usually have the capacity of transposition,
meaning that these elements have the ability to move and
change their location in the genome by using reverse tran-
scriptase . Relatively recently, still other remarkable re-
peated sequences were discovered in the human genome.
Human EndogEnous rEtrovirusEs
Human Endogenous Retrovirus-HERVs are polynucleotide
sequences representing the complete structure of the virus
[12,13]. Their structure consists of 2 long-terminal repeats
(LTR). Between them there are the gene encoding the struc-
tural proteins (gag), the genes encoding reverse transcrip-
tase, protease, ribonuclease, and integrase (pol), the gene
encoding the envelope proteins (env) and also the starter
tRNA binding region (the primer binding site-PBS) and so-
called packaging signal (Y) – which are important for the
function of the virus.
Human endogenous retroviruses (HERVs) were discov-
ered in the 1980. They represent about 8% of the human
genome [12,13] and are present in about 450 000 copies.
They can be classified into 200 different groups and sub-
groups. HERVs were integrated to germ-line cells of human
ancestors. It is estimated that such insertions have occurred
30 million years ago [12,13]. The presence of HERVs in the
human genome forms the basis for an argument for an al-
ternative theory of the evolution [14,15].
A specific type of HERVs can occur in the genome in a sin-
gle copy (eg, HRES-1), or can be repeated up to 1000 times
(eg, HERVs-H). The greatest concentration of HERVs se-
quences is found in chromosomes Y, X, 4 and 20.
Human endogenous viruses are one of the so-called retro-
elements, which are nucleotide sequences that can move
within the genome through a mechanism of “rewriting”
their composition to RNA sequence and incorporation of
Figure 1. Types of retro elements: pseudogene, retrogen, retropozon,
retrotranspozon, retrovirus. The meaning of symbols is as
follows.: LTR-long terminal repeats, P-promoter, AAAA-
adenine polynucleotide chain, ORF1-Open Reading Frame,
PBS-tRNA primer binding region (primer binding site),
gag-the gene encoding the structural proteins, pol-gene
encoding reverse transcriptase, env-the gene encoding the
Med Sci Monit, 2012; 18(6): RA80-88 Brodziak A et al – HERVs and autoimmune diseases
its “DNA equivalent” in another location of the genome by
action of reverse transcriptase. Retrogenes, retroposons and
retrotransposons are 3 types of retro-elements found in the
human genome [11,12].
Recently, the exogenous factors affecting the expression of
HERVs have been determined, their interactions with exoge-
nous retroviruses were examined, and the impact of HERVs
on the organization, functioning and evolution of the hu-
man genome has been considered [12–14].
data on tHE activity of Human EndogEnous
The majority of HERVs is not expressed, due to the numer-
ous inactivating mutations in the areas of reading frames.
These viruses are also frequently silenced by epigenetic
mechanisms (DNA methylation). Some of the HERVs are
active, however, and their expression is regulated by many
different factors. Some types of viruses HERVs are activated
by X-rays and ultraviolet light. This occurs in patients with
psoriasis. Pro-inflammatory cytokines, including IFN-alpha,
TNF-alpha and IL-1a and IL-1b, and glucocorticoids can act
as factors inducing activity of HERVs. Their expression is
highest in the placenta tissue and endocrine glands (hypo-
thalamus, male testes) [16–19].
Other factors influencing the activity of HERVs are prod-
ucts of exogenous viruses. For example, Epstein-Barr virus
enhances the transcription of the Env gene HERVs-K18 lo-
cated in the intron of the gene CD48 . In vitro studies
showed that HSV-1 induces expression of HERVs-W in hu-
man neuroblastoma cells. This virus also causes expression of
HERVs-K. Cytomegalovirus (CMV) is activated by HERVs-K.
The influenza virus causes increased levels of Env protein
HERVs in neuroepithelial cells .
Some of the HERVs are present in genes evolving rapidly
with a high incidence of mutations, as occurs in genes in-
volved in immune response processes.
Surprisingly, the products of the expression of HERVs also
have effects on physiological functioning and development
of tissues. Fang Li et al. wrote as follows: “A prominent ex-
ception, however, is the ERVWE1 locus on chromosome 7q.
This locus harbors a member of the HERV-W family with
an open reading frame in the env gene that encodes a pro-
tein denoted syncytin. This protein is highly expressed in
the syncytiotrophoblast layer of the human placenta and
appears to have been functionally adopted by the human
host for fusion of trophoblast cells and thus contributing
to the formation of the syncytiotrophoblast layer” [20–22].
Thus, HERVs are helpful for the proper formation of the
placenta and are involved in the suppression of rejection
of fetal tissues. HERVs also interfere with exogenous virus-
es through interference with their receptors or the forma-
tion of antisense mRNA and are also related to the devel-
opment of certain types of cancer [6,7,18].
sHort synopsis of tHE structurE and function of tHE
Human immunE systEm
The human body is constantly influenced by factors which
could harm it. These include toxins, bacteria, fungi, parasites
and viruses. The purpose of the immune system is to defend
against the constant stream of possible infections and toxins.
There are 2 branches of the immune system, called the
acquired immune system and the innate immune system.
The innate immune system protects the body without spe-
cial preparation. It consists of physical barriers formed by
skin, mucous membranes, saliva, flushing action of urine
and tears, and stomach acid. Another part of the innate im-
mune system is some elements present in the blood – phago-
cytes like neutrophils, macrophages, natural killer cells and
The acquired immune system needs to be primed before
it can work and it is only effective after it has seen a possi-
ble infective agent.
The acquired immune system is composed of 2 subsystems:
T-cell immunity (cell-mediated immunity) and B-cell immu-
nity (humoral immunity).
Cell-mediated immunity is realized by 3 kinds of lympho-
cytes: helper T-cells, cytotoxic T-cells, and regulatory T-cells
(T reg) (formerly termed suppressor T-cells).
B-cell immunity acts after exposure to the antigen and is
realized by “tuned” lymphoblasts, which transform them-
selves into plasma cells or clonal B-cells. Plasma cells pro-
duce antibodies. Clonal B-cells constitute immune memo-
ry. Antibodies can activate complement cascade.
T-cells work together with B lymphocytes. The function of
the helper T-cell is essential in the transition from detect-
ing an invader to launching a defense against it.
Also important is the cooperation of macrophages, cells
which metaphorically “eat” invaders.
Antibodies are molecules secreted by the B-cells and plas-
ma cells. They are immunoglobulins, which latch onto in-
vaders and neutralize them in various ways and also trigger
the production of cytokines. Cytokines are important mol-
ecules, components of the immune system. They are mo-
lecular signals emitted by lymphocytes and other cells. Cells
of the immune systems interact by means of cytokines or
T lymphocytes have receptors embedded in their membranes
(TCR). These receptors are composed of 2 proteins connect-
ed together. They are similar to immunoglobulins, but are
smaller. It is important to realize that T lymphocytes bind
not just an antigen, but a complex of an antigen associated
with a HLA protein. HLA proteins are molecules present
in most cells of the body, which allows to take a bits of the
antigen and hold it outside the cell so that it can checked
by T-cells. The contacts between T-cells and other cells are
usually performed in cooperation with some specific sur-
face proteins (Figure 2).
Human LEukocytE antigEn
The human leukocyte antigen (HLA) system is the major
histocompatibility complex (MHC) in humans. The group
Review Article Med Sci Monit, 2012; 18(6): RA80-88
of genes from the locus on chromosome 6 contains a large
number of genes related to immune system function in hu-
mans. This group of genes encodes cell-surface antigen-pre-
The HLA genes are the human versions of the MHC genes
that are found in most vertebrates. HLA class I antigens
present peptides from inside the cell, including viral pep-
tides. Foreign antigens attract killer T-cells, also called CD8-
positive or cytotoxic T-cells, which destroy cells. HLA class
II antigens present antigens from outside of the cell to
T-lymphocytes. These particular antigens stimulate T-helper
cells to multiply, and these T-helper cells then stimulate an-
tibody-producing B-cells to produce antibodies to that spe-
cific antigen (Figure 2).
So HLA (Human Leukocyte Antigen) is a class of proteins
which is found on the surface membrane of cells, and which
are “presenting” possible antigen to T- and B-cells. They are
also present inside a cell, and have a groove in which they
can attach little bits of protein. These bits of protein will
have come from outside the cell or could be products of
the cell’s own genes. Once a bit of protein or other possi-
ble antigen is attached, the HLA moves out and protrudes
from the outside of the cell, so that a T-cell can come along
and check the molecule that is being presented.
The T-cells, in turn, check whether the molecule is self or
foreign, and will pass over it or react to its presence, either
destroying the cell, or raising the alarm about the foreign
substance by emitting cytokines.
T-cells can be distinguished from other types of lymphocyte by
the presence of a special receptor on their cell surface, called
T-cell receptors (TCR). The shape and function of the T-cell
receptor is variable. There are millions of different types of
T-cell receptors in the body, and each of them is specialized
to recognize different “foreign” matter. There are also recep-
tors that would attack the body’s own proteins and cells but
these are checked and destroyed in the thymus, where the
T-cells mature, before the T cells are let loose in the body.
The helper T-lymphocytes are crucial to the function of
the immune system. They assist other white blood cells in
maturation of B-cells into plasma cells and B memory cells,
and activation of cytotoxic T-cells and macrophages. Helper
T-cells circulate throughout the body and check for antigens
that might be signs of invasion by viruses or bacteria. They
interface with HLA class II protein on other cells (antigen
presenting cells-APCs), checking what kind of substance
HLA class II is presenting. If the helper T-cell is stimulated
by contact with antigen, it responds by cell division, as well
as producing lymphokines and chemokines. Lymphokines
and chemokines are chemical messages that transfer sig-
nals to other cells. Cell division results in more and more
activated helper T-cells.
The helper T-cells are the main cells that carry the CD4 sur-
face protein. It is the main type of cell targeted by HIV. The
virus can destroy the majority of CD4+ cells in the human
immune system and the immune system is then paralyzed.
The cytotoxic T-cells are known also as killer T-cells or CD8+
T-cells, as they express the CD8 glycoprotein at their surface.
They destroy virally infected cells and tumor cells, and are also
implicated in transplant rejection. Viral and other foreign
peptides are processed by the MHC class I, which is present
on the surface of nearly every cell of the body. A piece of for-
eign antigen is protruded to the outside of the cell by HLA
protein. A cytotoxic T-cell then binds to such a cell by an in-
teraction between CD8, TCR (T-cell receptor) and HLA. If
the peptide presented to the cytotoxic T-cell by HLA fits the
cleft in the TCR, then a chemical signal is triggered within
the T cell, which causes it to attack and destroy the infect-
ed cell. Through IL-10, adenosine and other molecules se-
creted by regulatory T-cells, the CD8+ cells can be inactivat-
ed to an anergic state, which prevent autoimmune diseases.
Memory T-cells are a subset of antigen-specific T-cells that
persist long-term after an infection has resolved. They quick-
ly expand to a large numbers of T-cells upon re-exposure to
the antigen. They constitute the immune system’s “memo-
ry” of past infections.
Regulatory T-cells (T reg Cells)
T reg cells formerly known as suppressor T-cells, are im-
portant for the maintenance of immunological tolerance.
Their major role is to block T-cell-mediated immunity to-
ward their own cells. Two major classes of CD4+ regulato-
ry T cells have been described – the naturally occurring T
reg cells and the adaptive T reg cells. Naturally occurring T
reg cells can be distinguished from other T-cells by the pres-
ence of an intracellular molecule called FoxP3.
CD4 Cell surface protein
CD4 is a glycoprotein found mainly on surface of the ma-
ture helper T cells, macrophages and on some cytotoxic T
cells. About 65% of T-cells in the blood are CD4+ with CD4
Figure 2. Cooperation of cytotoxic and helper T lymphocytes with HLA
proteins of class I and class II of antigen presenting cells (APC).
Med Sci Monit, 2012; 18(6): RA80-88 Brodziak A et al – HERVs and autoimmune diseases
protein protruding from their membrane. Mature T-cells
have CD4 or CD8, but not both. CD4 is a member of the
immunoglobulin superfamily. The external part of the pro-
tein has 4 “domains” and these are the essential part of the
protein composed from 433 amino acids.
CD4 cooperates with HLA protein of different cells to al-
low helper T-cells to check for ‘suspicious’ proteins of these
cells. Normal CD4+ counts are between 500 and 1600, but
a person with HIV/AIDS commonly has a CD4+ count of
less than 200.
CD8 cell surface protein
CD8 is also a cell surface protein found predominantly
on T-cells. CD8 is ordinarily found on the surface of killer
T-cells, as opposed to CD4, which is ordinarily found on the
surface of helper T-cells. CD8 cooperates with HLA class I,
which allows the T-cell receptor protein to dock to HLA-I
and check the antigen that HLA is presenting. If the shape
of the T-cell receptor matches the antigen that is being pre-
sented, then a sequence of signals is triggered inside the
T-cell which causes it to kill the cell to which it is attached.
The T-cell receptor exists as a complex of several proteins.
TCR is composed of 2 separate peptide chains, which are
produced from the independent T-cell receptor alpha and
beta (TCRa and TCRb) genes. TCR interfaces with major
histocompatibility complex protein (HLA) to “feel” the
shape of a protein presented by MHC.
immunoLogicaL pHEnomEna and concEpts rELatEd to
patHogEnEtic mEcHanisms of autoimmunE disEasEs
Tolerance is the ability of the normal immune system to rec-
ognize and respond to foreign antigens, but not to self an-
tigens. Autoimmunity is evoked when this tolerance to self
antigen is broken. The tolerance of a person is formed al-
ready in the fetus. During this period of life, maternal-fe-
tal tolerance exists.
The pre-T-cells leave the bone marrow, where they were syn-
thesized. They move to the thymus, where the maturation
of T-cells occurs and the first step of T-cell tolerance is real-
ized. Within the thymus, pre-T-cells encounter various self
and foreign antigens and pre-T-cells undergo a double se-
lection process. They must be positively selected and should
avoid negative selection. A T-cell is positively selected when
it binds with low affinity to self-MHC receptors. Other T-cells
are eliminated by apoptosis. Cells that survive positive selec-
tion, but bind strongly to self-antigens, are negatively select-
ed and are also eliminated by induction of apoptosis. This
negative selection is known as clonal deletion.
T-cell tolerance must be developed further in the periphery,
because there is only a limited repertoire of antigen that
T-cells can encounter within the thymus. This same positive
and negative selection mechanism is applied in peripheral
tissues. This is known as clonal anergy. Another mechanism
of T-cell tolerance is known as active suppression.
Autoimmune diseases are characterized by long, asymptom-
atic prodromal periods. The initiating events causing the
loss of self tolerance occur long before the disease clinical-
ly manifests; therefore, it is difficult to recognize the initi-
ating factors, which remain largely unknown.
Autoimmunity results from of a loss of immunological tol-
erance, which is the ability for an individual to discriminate
between self and non-self. In another words, it is the failure
to recognize self antigens as “self”.
Foreign agents are pathogens like bacteria and viruses that
can induce autoimmunity by polyclonal activation of B- or
T-cells or increased expression of the class I or II molecules
of the major histocompatibility complex (MHC). There are
some different ways in which a pathogen can cause an au-
toimmune response. The pathogens may contain a protein
that acts as a mitogen to encourage cell division, thus caus-
ing intensified production of B- or T-cell clones. A pathogen-
ic protein may act as a superantigen (see below), which can
induce rapid polyclonal activation of B- or T-cells. Pathogens
can also cause the release of cytokines, resulting in the ac-
tivation of B- or T-cells, or they can alter macrophage func-
tion. Pathogens may also expose B- or T-cells to cryptic de-
terminants that induce the molecular mimicry mechanism.
These are a class of antigens that cause non-specific activa-
tion of T-cells. This activation induces polyclonal T-cell acti-
vation and massive cytokine release. SAgs can be produced
by viruses, mycoplasma, and bacteria. Compared to a nor-
mal antigen-induced T-cell response, where about 0.001%
of the body’s T-cells are activated, the SAgs are capable of
activating up to 20% of the body’s T-cells.
The large number of activated T-cells secretes large amounts
of cytokines, especially TNF-alpha. When TNF-alpha is re-
leased in the blood in high doses it can cause severe and
life-threatening symptoms, including shock and multiple
Typical antigens are captured by the antigen presenting cell
(APC), which processes them and places them within the
histocompatibility complex (MHC) class II on their surface.
In this form the antigen is presented to T lymphocytes. In
the case of spatial matching of antigen, MHC II, and T-cell
receptor (TCR), the Tc lymphocyte is activated (Figure 1).
This means that in case of detecting the presence of a for-
eign protein, the activation occurs and a precise, specific
T-cell clone multiplies. In the case of the presence of a su-
perantigen, unlike the typical situation described above,
SAg activates T lymphocytes in a nonspecific manner, cre-
ating a kind of “short circuit” between the MHC II and
b-chain of T-cell receptors (Figures 3 and 4), a non-specif-
ic activation and division of numerous clones of T-cells, al-
though the place of presentation of antigen on MHC II re-
mains empty. Normally, 5–10% of all cells have receptors
containing the b chain, but in the presence of SAgs this per-
centage grows rapidly due to the expansion of stimulated
cells. Stimulated cells produce cytokines, especially interleu-
kin-4 and interleukin-13. Staphylococcal enterotoxins also
Review Article Med Sci Monit, 2012; 18(6): RA80-88