autoimmune diseases ( aids ) are chronic disorders originated by the loss of immunological tolerance to self - antigens .
this heterogeneous group of conditions present common genetic risk factors and share several pathophysiological mechanisms leading to overlapping clinical manifestations targeting specific organs or multiple organ systems .
there is evidence that they share similar immunogenetic mechanisms , even though they exhibit varying epidemiological features and clinical manifestations [ 2 , 3 ] .
underlying these diverse clinical phenotypes is a deregulated immune system with an enriched ability to respond against self - tissues .
the fact that aids share several clinical signs and symptoms ( i.e. , subphenotypes ) and also share physiopathological mechanisms and genetic factors has been called autoimmune tautology and indicates that they may have a common origin .
the immune system is in charge of the defence against external pathogens . for this purpose , t and b lymphocytes
are responsible for the immune response through regulated cell - cell interactions and secretion of cytokines , chemokines , and other inflammatory mediators .
this defence against external pathogens must occur without causing unnecessary harm to self . to achieve this delicate balance ,
the majority of self - reactive t and b lymphocytes are destroyed in the thymus and bone marrow through negative selection .
nevertheless , this process is far from perfect , and self - reactive lymphocytes escape into the periphery .
consequently , peripheral tolerance mechanisms are necessary to keep these self - reactive cells in check .
activated self - reactive t and b cells promote autoimmunity when the effector and regulatory balance of the immune response is disturbed .
major histocompatibility complex ( mhc ) molecules are widely distributed surface membrane glycoproteins that present antigenic peptides to t cell receptors ( tcrs ) . developing thymocytes encounter a highly heterogeneous repertoire of self ( endogenous ) peptide - mhc ( pmhc ) complexes on thymic epithelial cells , the main thymus antigen presenting cells . the affinity / avidity with which these thymocyte tcrs bind self pmhc determines if it is destined to perish or if it will survive . in this way , a repertoire of peripheral t cells that is essentially self - tolerant
several hypotheses have been put forward to explain how mhc polymorphisms influence autoimmunity risk or protection .
they must do so , somehow , by shaping the central or peripheral t cell repertoires toward autoimmune resistance or proclivity .
a protective mhc profile could achieve this by the selection of a t cell repertoire with diminished pathogenicity . on the other hand , protective mhc molecules
may keep autoimmunity in check by favouring the negative selection of particular self - reactive t cells [ 1214 ] .
the functional basis of the association between specific hla alleles and development of aids can be classically explained by two possible etiopathogenic models . 

the molecular mimicry hypothesis proposes that certain hla alleles are more efficient in presenting pathogen epitopes that share structural features with self - peptides to mature t cells .
once the response to the pathogen is initiated the self - antigen is also recognized and disease ensues . 

central selection failure proposes that certain hla alleles are less efficient at presenting self - peptides to developing t cells in the thymus , so negative selection fails .
a different hypothesis proposes that different alleles can modulate the immunologic profile of an individual , through antigen - independent mechanisms , resulting in either promoting a higher autoimmune predisposition or , in opposition , a more efficient immune regulation .
given the consistent association of hla - drb1 alleles with different autoimmune diseases ( table 1 ) , we explored the idea that the same hla - drb1 alleles could be influencing several different autoimmune diseases . to this end
this study includes four autoimmune systemic diseases , namely , systemic lupus erythematosus ( sle ) , rheumatoid arthritis ( ra ) , psoriasis or psoriatic arthritis ( ps + psa ) , and systemic sclerosis ( ssc ) .
patients with multiple sclerosis ( ms ) and myasthenia gravis ( mg ) were also included .
a total of 1228 patients with aids , 213 patients with sle and 153 patients with ra diagnosed according to the american college of rheumatology ( acr ) criteria , 166 patients with ps + psa , 67 with ssc , 536 with definitive diagnosis of ms according to the revised mcdonald criteria , and 93 with mg , were recruited from the neurology and medicine outpatient clinic of centro hospitalar do porto - hospital de santo antnio ( chp - hsa ) .
the hla - drb1 frequencies of patients were compared with the ones of a control group consisting of 282 unrelated individuals without disease and from the same geographic origin ( north of portugal ) .
genomic dna was obtained from proteinase - k  treated peripheral blood leukocytes by using a salting - out procedure .
drb1 locus ( i.e. , 2-digit hla nomenclature ) was performed using polymerase chain reaction and sequence - specific primers ( pcr - ssp ) , based on methods previously described . in order to produce pcr - ssp reactions able to detect and discriminate each of the known hla - drb1 genes ,
primers were designed using sequence alignments comprising all hla - drb1 variants and were validated by the twelfth international histocompatibility workshop .
pcr products were visualized under ultraviolet light after running in a 1.5% agarose gel containing ethidium bromide . to identify the hla - drb1 genes contributing to the six different aids
, we applied stepwise logistic regression on an allelic level , using forward selection which involves starting with no variables in the model , testing the addition of each variable using a chosen model comparison criterion , adding the variable ( if any ) that improves the model the most , and repeating this process until none improves the model .
it should be noted that odds ratios ( ors ) obtained in a multivariable logistic regression analysis are adjusted for all the other genes included in the model and therefore differ from those obtained when a given gene is compared with all other genes .
a total of 1228 cases and 282 controls were analysed and different types of association between alleles and aids were found ( table 2 ) .
these included three risk alleles for two or more aids , two protective alleles for two or more aids , and three risk alleles for a particular aid .
hla - drb113 was a protective allele for four aids : sle ( 18.3% versus 29.8% , p = 0.016 , or = 0.58 , and 95% ci = 0.370.90 ) , ps + psa ( 19.3% versus 29.8% , p = 0.050 , or = 0.621 , and 95% ci = 0.391.00 ) , ra ( 16.3% versus 29.8% , p = 0.044 , or = 0.58 , and 95% ci = 0.340.98 ) , and ssc ( 11.9% versus 29.8% , p = 0.035 , or = 0.42 , and 95% ci = 0.190.94 ) .
hla - drb103 was found to be a risk factor for sle ( 34.3% versus 15.6% , p = 4.2  10 , or = 2.49 , and 95% ci = 1.613.86 ) , ms ( 22.9% versus 15.6% , p = 0.003 , or = 1.81 , and 95% ci = 1.232.67 ) , and mg ( 35.5% versus 15.6% , p = 6.1  10 , or = 2.98 , and 95% ci = 1.755.07 ) .
there were two risk alleles associated with two aids : hla - drb108 was positively associated with ms ( 12.1% versus 8.5% , p = 0.033 , or = 1.73 , and 95% ci = 1.052.87 ) and ssc ( 22.4% versus 8.5% , p = 0.004 , or = 3.01 , and 95% ci = 1.436.31 ) and hla - drb101 was found to be a risk factor for ra ( 32.7% versus 23.4% , p = 0.017 , or = 1.79 , and 95% ci = 1.112.88 ) and ssc ( 41.8% versus 23.4% , p = 0.006 , or = 2.28 , and 95% ci = 1.274.09 ) .
hla - drb109 was negatively associated with sle ( 1.0% versus 5.0% , p = 0.027 , or = 0.18 , and 95% ci = 0.040.83 ) , ms ( 1.0% versus 5.0% , p = 0.004 , or = 0.22 , and 95% ci = 0.080.63 ) , and ra ( 0.0%
versus 1.0% , p = 0.003 , or = 0.95 , and 95% ci = 0.930.98 ) .
three risk disease - specific alleles were found : hla - drb104 for ra ( 47.7% versus 24.5% , p = 6  10 , or = 2.81 , and 95% ci = 1.794.39 ) , hla - drb107 for ps + psa ( 39.8% versus 25.5% , p = 0.006 , or = 1.79 , and 95% ci = 1.182.72 ) , and hla - drb115 for ms ( 32.7% versus 19.9% , p = 2  10 , or = 2.17 , and 95% ci = 1.533.10 ) .
considering aids as a group , hla - drb103 frequency was significantly higher ( 23.9% versus 15.6% , p = 0.022 , or = 1.51 , and 95% ci = 1.02.15 ) compared with controls ; conversely hla - drb113 ( 20.0% versus 29.8% , p = 0.004 , or = 0.58 , and 95% ci = 0.430.79 ) and hla - drb109 ( 1.4% versus 5.0% , p = 1  10 , or = 0.23 , and 95% ci = 0.110.49 ) frequencies were significantly lower .
through a systematic review of published works , cruz - tapias and collaborators , in 2012 , identified some common hla class ii alleles that contribute to susceptibility to aids in latin americans .
the present study is , to date and to the best of our knowledge , the only one that addresses the hypothesis that a hla - drb1 allele could influence different autoimmune diseases , using a new cohort , encompassing six different autoimmune diseases . in this study
we confirmed positive and negative associations in ms [ 24 , 25 ] , sle [ 1618 ] , ps + psa [ 19 , 20 ] , ra , ssc [ 22 , 23 ] , and mg , previously reported in our or other populations . when aids studied were considered as a group , hla - drb103 allele was significantly overrepresented , as already described .
it has been shown that this allele has low affinity for clip ( class ii - associated invariant chain peptide ) and may not require hla - dm to ensure peptide presentation , preventing efficient peptide selection and allowing the binding of low stability peptides . concerning the observed negative association with hla - drb109
, we think that this is likely a spurious association , as this is a rare allele and the frequency found in controls is , for some reason , double the one reported for the portuguese population .
our observations suggest that the presence of hla - drb113 allele may confer protection for aids .
hla - drb113 is a high frequency allele in the general population both in portugal   and worldwide .
our results confirm that the lower frequency of hla - drb113 in every individual aids group is not secondary to the deviations granted by the concurrent positive associations .
when the data obtained from previous studies are taken into consideration , the hla - drb113 allele seems to be a universal protective allele for ra .
it was reported as protective against ra in asian [ 32 , 33 ] , turkish , and several european populations [ 3537 ] . recently
this allele was also described to be protective in sle in the japanese population   and for anca - associated vasculitis in the dutch population .
specific amino acid patterns at the peptide binding cleft are involved in disease susceptibility , such as the well - known shared epitope first described in the ra susceptibility alleles hla - drb101 and hla - drb104 [ 37 , 39 ] .
similar to the shared epitope classification of susceptibility alleles , protective hla - drb1 alleles have been categorized according to several models .
one of the most accepted classifications proposes that protection against ra is conferred by the deraa sequence at positions 7074 of the hla - drb1 allele .
other models suggest that protection is conferred by an aspartic acid at position 70 ( d70 allele )   or an isoleucine at position 67 ( i67 allele ) of the hla - drb1 molecule . because it was unclear which hla - drb1 alleles were protective a meta - analysis was performed involving four european populations with > 2,700 patients and > 3,000 control subjects .
the objective was to investigate exhaustively which hla - drb1 alleles were associated with protection against ra .
interestingly , this study showed that the protective effect attributed to deraa and d70 was no longer present after the exclusion of hla - drb113 .
the authors concluded that this evidence indicates that hla - drb113 rather than deraa , d70 , or i67 is associated with protection . in a recent study van heemst and
collaborators identify citrullinated vinculin , present in the joints of acpa ra patients , as an autoantigen targeted by acpa and cd4 t cells .
these t cells recognize an epitope with the core sequence deraa , which is also found in many microbes and in protective hla - drb113 molecules , presented by predisposing hla - dq molecules .
intriguingly , deraa - directed t cells were not detected in hla - drb113 donors , indicating that the deraa epitope from hla - drb113 could mediate thymic tolerance in these donors and explain the protective effects associated with hla - drb113 .
they suggest that subjects born with hla - drb113 will present the hla - drb113-derived deraa - peptide in the thymus , leading to tolerization of the deraa - reactive t cell response .
the negative association we describe here supports the idea that the hla - drb113 allele , possibly by its specific structural features , may as well confer resistance to several other aids .
the protective effect of hla - drb113 could be explained by a more proficient antigen presentation by these molecules [ 43 , 44 ] , favouring an efficient thymic selection . as a result , negative selection and development of dr - driven autoreactive regulatory t cells
a different model would relate hla molecules with the presence of specific endophenotypes indirectly associated with autoimmunity .
other studies of our group suggest that the hla genotype may primarily influence the general activation state of cd4 t cells . the protective effect of hla - drb113
curiously , several reports have suggested an association of hla - drb113 and/or hla - dqb106 with slow disease progression in human immunodeficiency virus ( hiv ) infected individuals , meaning that among hiv controllers there is an association between the presence of certain class ii hla alleles and strong cd4 t cell responses [ 46 , 47 ] .
although different alleles are associated with particular aids , the same allele , hla - drb113 , was underrepresented in all six diseases .
this observation suggests that this allele confers protection to aids in general and particularly to rheumatic diseases .
 autoimmune diseases ( aids ) are characterized by a multifactorial aetiology and a complex genetic background , with the mhc region playing a major role . 
 we genotyped for hla - drb1 locus 1228 patients with aids-213 with systemic lupus erythematosus ( sle ) , 166 with psoriasis or psoriatic arthritis ( ps + psa ) , 153 with rheumatoid arthritis ( ra ) , 67 with systemic sclerosis ( ssc ) , 536 with multiple sclerosis ( ms ) , and 93 with myasthenia gravis ( mg ) and 282 unrelated controls . 
 we confirmed previously established associations of hla - drb115 ( or = 2.17 ) and hla - drb103 ( or = 1.81 ) alleles with ms , hla - drb103 with sle ( or = 2.49 ) , hla - drb101 ( or = 1.79 ) and hla - drb104 ( or = 2.81 ) with ra , hla - drb107 with ps + psa ( or = 1.79 ) , hla - drb101 ( or = 2.28 ) and hla - drb108 ( or = 3.01 ) with ssc , and hla - drb103 with mg ( or = 2.98 ) . 
 we further observed a consistent negative association of hla - drb113 allele with sle , ps + psa , ra , and ssc ( 18.3% , 19.3% , 16.3% , and 11.9% , resp . 
 , versus 29.8% in controls ) . 
 hla - drb113 frequency in the aids group was 20.0% ( or = 0.58 ) . 
 although different alleles were associated with particular aids , the same allele , hla - drb113 , was underrepresented in all of the six diseases analysed . 
 this observation suggests that this allele may confer protection for aids , particularly for systemic and rheumatic disease . 
 the protective effect of hla - drb113 could be explained by a more proficient antigen presentation by these molecules , favouring efficient clonal deletion during thymic selection . 
1. Introduction
2. Patients and Methods
3. Results
4. Discussion