Varicella Zoster Virus Seropositivity
Varicella zoster virus (VZV) seropositivity refers to the presence of antibodies against the varicella zoster virus in an individual's blood. VZV is a highly contagious human herpesvirus responsible for two distinct clinical manifestations: primary infection, known as chickenpox (varicella), and reactivation, known as shingles (herpes zoster). [1] Seropositivity indicates that an individual has previously been exposed to the virus, either through natural infection or vaccination, and has developed an immune response.
Biological Basis
The immune system's response to VZV involves the production of specific antibodies, such as IgG, which can be detected in the bloodstream. These antibodies are crucial for long-term immunity and are indicative of prior exposure. Genetic factors play a significant role in shaping an individual's immune response to VZV. Research indicates that variants within the Major Histocompatibility Complex (MHC) region, particularly genes like HLA-DQA1, HLA-DRB6, HLA-DRB1, and HLA-DQB1, are associated with VZV seropositivity and the levels of VZV-specific antibodies. [2] Genetic polymorphisms in these immune system genes can influence viral latency and the strength and nature of the host's immune response, affecting susceptibility to both primary infection and reactivation. [1] For instance, the HLA-B gene region on chromosome 6 has been linked to herpes zoster. [3]
Clinical Relevance
Understanding VZV seropositivity is clinically important for several reasons. It helps assess an individual's immune status and their susceptibility to chickenpox if not previously infected or vaccinated. While seropositivity generally confers protection against primary infection, it does not prevent viral reactivation in the form of shingles, which can occur years or decades after the initial infection. Genetic studies identifying associations between specific variants and VZV immune responses can inform personalized risk assessments for herpes zoster and potentially guide the development of targeted preventive or therapeutic strategies. [1]
Social Importance
VZV has historically been a pervasive public health concern globally. Before the widespread availability of the varicella vaccine, the vast majority of adults in many countries experienced VZV infection, typically as children. [1] Assessing population-level VZV seropositivity is vital for public health surveillance, monitoring vaccine effectiveness, and identifying communities at higher risk for outbreaks. Insights into the genetic determinants of VZV immune responses contribute to a broader understanding of human genetic variation in infectious disease susceptibility, impacting vaccine development and public health interventions.
Limitations in Population Scope and Generalizability
The primary genetic analysis was restricted to White British individuals, a methodological choice made to minimize bias stemming from population stratification. [2] While important for study rigor, this approach inherently limits the generalizability of the findings to more diverse ancestral groups. [2] The genetic determinants influencing varicella zoster virus seropositivity identified within this specific cohort may not exhibit the same relevance or effect sizes in other populations, thereby impacting the broader applicability of the research. [2] Therefore, further studies involving diverse populations are essential to confirm and extend these genetic associations globally.
Phenotypic Definition and Serological Measurement Considerations
Interpreting serological test results for varicella zoster virus (VZV) seropositivity presents several complexities. [2] A negative test result may signify a lack of prior exposure to the infectious agent, an inability of the host to mount an antibody-mediated immune response, or that antibodies are not always a precise indicator of past contact or current immune status. [2] Conversely, a positive antibody titer, particularly if low, could potentially arise from cross-reactivity with other non-specific antigens. [2] Antibody levels are also known to fluctuate over time due to various host and environmental factors, which complicates the consistent and accurate quantification and interpretation of antibody-mediated responses. [2] For VZV specifically, it is challenging to differentiate between protection from a primary infection, extended viral latency, or protection from viral re-emergence based solely on seropositivity, all of which could influence the risk of a clinical diagnosis of herpes zoster. [4] Furthermore, heavily skewed Mean Fluorescence Intensity (MFI) data in quantitative analyses risked inflating variance and violating linear regression assumptions, necessitating logarithmic transformations to ensure reliable results. [2]
Statistical Power, Replication Gaps, and Unaccounted Factors
The statistical power to detect robust genetic associations for varicella zoster virus seropositivity was significantly constrained, as this analysis had one of the smallest sample sizes in the study, including only 1371 individuals. [2] Such limited sample sizes, when combined with potential genomic inflation, raise concerns about an elevated rate of false-positive associations and the overall reliability of the identified loci. [2] Beyond the major histocompatibility complex (MHC) region and the FUT2 gene, few other genetic loci were consistently replicated across different infectious agents or even within infectious agent families, suggesting potential effect-size inflation or the necessity for independent replication cohorts to validate the findings. [2] Moreover, the current research does not fully account for the intricate interplay of environmental exposures or gene-environment interactions that influence VZV immune responses, contributing to the "missing heritability" phenomenon and an incomplete understanding of the trait's full genetic architecture. [5] It is also acknowledged that the results for VZV associations have not yet undergone replication, underscoring the need for future validation studies to confirm the reported findings. [4]
Variants
The HLA-DQB1 gene is a critical component of the Major Histocompatibility Complex (MHC) class II region, located on chromosome 6. This gene encodes a beta chain that, when paired with an alpha chain from the HLA-DQA1 gene, forms an MHC class II protein. These proteins are vital for the immune system, as their primary function is to present processed antigens, derived from extracellular proteins, to T-helper lymphocytes, thereby initiating adaptive immune responses against various pathogens. [2] Variants such as rs1766 can influence the expression or function of HLA-DQB1, potentially altering the efficiency of antigen presentation and modifying an individual's susceptibility or response to infectious agents, including the varicella zoster virus.
The HLA-DQB1 gene and its specific alleles significantly influence the strength and character of antibody-mediated immune responses to viruses. For example, the HLA-DQB1*02:01 allele has been directly associated with varicella zoster virus (VZV) antibody mean fluorescence intensity (MFI), indicating its role in determining the level of VZV-specific antibodies produced. [2] This allele also shows associations with antibody responses to Epstein-Barr virus (EBV), affecting EA-D and EBNA antibodies, suggesting a broader involvement in antiviral immunity. [2] The ability of HLA-DQB1 molecules to bind and present specific VZV glycoproteins, such as Glycoproteins E and I, to T cells is crucial for mounting an effective immune response and achieving seropositivity, making variations in this gene important determinants of VZV immunity. [2]
Adjacent to HLA-DQB1 is HLA-DQB1-AS1, an antisense RNA gene. Antisense RNAs are known to regulate the expression of their nearby protein-coding genes through various mechanisms, including transcriptional interference or modulation of messenger RNA stability. Thus, HLA-DQB1-AS1 likely plays a role in fine-tuning the expression levels of the HLA-DQB1 gene, which in turn impacts the quantity of MHC class II molecules available for antigen presentation. [6] A variant like rs1766, if located within HLA-DQB1-AS1 or its regulatory regions, could alter this delicate regulatory control, leading to changes in HLA-DQB1 expression. Such alterations could ultimately affect the immune response to pathogens like VZV, influencing an individual's seropositivity and antibody levels, as the availability of functional HLA-DQB1 proteins is a critical factor in effective immune recognition. [2]
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs1766 | HLA-DQB1-AS1, HLA-DQB1 | varicella zoster virus seropositivity |
Definition and Fundamental Terminology
Varicella zoster virus seropositivity denotes the presence of detectable antibodies specific to the varicella zoster virus (VZV) in a person's blood serum or plasma. VZV, a member of the Herpesviridae family, is the causative agent of chickenpox (varicella) and shingles (herpes zoster) . This method has been validated for determining seropositivity thresholds for various infectious agents, including VZV. [2] For instance, seropositive status can be defined by specific absorbance values, such as an MFI of 1.1 or greater, while values below 0.9 are considered seronegative, and those between 0.9 and 1.1 are indeterminate. [7]
While a positive antibody titer generally indicates prior exposure to VZV or vaccination, it requires careful interpretation. Low antibody titers might be attributed to cross-reactivity with other antigens, potentially leading to misinterpretation. [2] Conversely, a negative serological test does not definitively rule out VZV exposure; it could mean the individual has never encountered the virus, or the host was unable to mount an antibody-mediated response. [2] Furthermore, antibody levels can fluctuate over time due to various host and environmental factors, adding complexity to the diagnostic assessment. [2]
Genetic Factors Influencing Immune Response and Susceptibility
Genetic testing plays a significant role in understanding an individual's susceptibility to VZV infection and the subsequent immune response, particularly to herpes zoster (shingles), which is a reactivation of VZV. Genetic polymorphisms within immune system genes, especially those in the major histocompatibility complex (MHC) region, can influence viral latency and the immune system's ability to respond to the virus. [4] Genome-wide association studies (GWAS) have identified common genetic variants associated with herpes zoster diagnoses by analyzing electronic medical records. [4]
Specific genetic variants, such as rs17843569 in HLA-DQA1, rs55792153 in HLA-DRB1, rs28393149 in HLA-DRB6, and rs11881343 in HLA-DQB1, have been associated with VZV seropositivity or antibody levels (MFI). [2] Additionally, variants on chromosome 3p29 and within the HLA-B locus on chromosome 6 have shown genome-wide significance for association with herpes zoster, confirming previous GWAS findings. [3] Analyzing amino acid residue sequences within highly polymorphic HLA genes can provide a more powerful and informative statistical analysis for understanding disease associations than studying alleles alone. [2]
Clinical Presentation and Differential Diagnosis of Varicella Zoster Reactivation
Although VZV seropositivity itself is an asymptomatic laboratory finding, its presence indicates a past infection, which carries the risk of VZV reactivation, manifesting clinically as herpes zoster. Clinically, herpes zoster typically presents as a painful, usually unilateral, vesicular skin infection distributed along a dermatome. [4] This condition can lead to complications such as postherpetic neuralgia, and has been identified as a risk factor for cerebrovascular disease and myocardial infarction. [4]
When evaluating for active herpes zoster, distinguishing it from other conditions that cause similar skin lesions is crucial. While the characteristic dermatomal rash is often indicative, other viral infections or dermatological issues might present similarly. Risk factors for herpes zoster reactivation include age, being female, certain ancestries, and a family history of the disease. [4] The presence of VZV antibodies confirms prior exposure, setting the stage for potential reactivation, and helps in differentiating VZV-related symptoms from those caused by other pathogens.
Varicella Zoster Virus Infection and Immune Response
Varicella zoster virus (VZV) is a human herpesvirus responsible for two distinct clinical manifestations: primary infection, known as chickenpox (varicella), and reactivation, known as herpes zoster (shingles). [1] Following primary infection, VZV establishes a lifelong latent infection within sensory ganglia, where the viral genome persists without active replication. Varicella zoster virus seropositivity refers to the presence of detectable antibodies against VZV in the blood, indicating prior exposure to the virus and the host's antibody-mediated immune response. [2] This serological status can be quantified by measuring antibody levels, such as mean fluorescence intensity (MFI), or assessed dichotomously as seropositive versus seronegative. [5] The vast majority of adults in the United States have experienced VZV infection, typically as children, before the widespread availability of the varicella vaccine. [1]
Genetic Influence on Antigen Presentation and Antibody Production
The host's ability to mount an effective antibody-mediated immune response to VZV is significantly influenced by genetic factors, particularly within the Major Histocompatibility Complex (MHC) region, also known as the Human Leukocyte Antigen (HLA) region. Genes like HLA-DQA1, HLA-DRB6, HLA-DRB1, and HLA-DQB1 encode critical proteins involved in presenting viral antigens to T-cells, thereby initiating and shaping the adaptive immune response. [2] Specific genetic variants within these HLA genes have been associated with varicella zoster virus seropositivity and the quantitative levels of antibodies produced against VZV antigens. For instance, the rs17843569 variant in HLA-DQA1 and rs11881343 in HLA-DQB1 are linked to VZV seropositivity, while rs374949924 in HLA-DRB6 and rs55792153 in HLA-DRB1 influence antibody levels against the VZV VP1 protein. [2] Furthermore, rs11881343 in HLA-DQB1 is also associated with the mean fluorescence intensity of antibodies targeting VZV Glycoproteins E and I, highlighting the role of these HLA alleles in determining the specificity and magnitude of the antibody response to key viral structural components. [2]
Molecular and Epigenetic Regulation of Viral Pathogenesis
Beyond the direct influence of HLA genes on antigen presentation, other molecular and cellular pathways contribute to the host's ability to control VZV infection and prevent reactivation. Genetic polymorphisms in immune system genes can impact viral latency and the level of viral productivity. [1] For example, specific genomic regions involved in regulatory functions, such as those encompassing the HCP5 gene within the HLA complex, are linked to the risk of viral reactivation. [1] Moreover, epigenetic modifications, like the histone H3K4me3 peak, and the binding of transcription factors such as FOS, STAT3, and TCF7L2, have been observed in genomic regions associated with the herpes zoster phenotype. [3] These regulatory elements, including DNAase I hypersensitivity sites, suggest that complex gene expression patterns and chromatin remodeling events play a crucial role in regulating VZV latency and reactivation, potentially by influencing the transcription of host genes critical for antiviral defense or viral gene expression. [3]
Pathophysiological Processes of Herpes Zoster
Following primary VZV infection, the virus establishes latency in nerve ganglia, maintaining a dormant state for years or even decades. The reactivation of this latent virus leads to herpes zoster, characterized by a painful rash typically in a dermatomal distribution. [1] Genetic variants, particularly those within the HLA region, are associated with susceptibility to herpes zoster, indicating a host genetic influence on the risk of viral reactivation. [1] Understanding the molecular and cellular mechanisms that regulate viral latency and subsequent reactivation, including the interplay between viral and host genetic factors, is crucial for developing clinical strategies to prevent or treat this disease. [1] Factors such as older age, female sex, and European ancestry have also been consistently associated with an increased risk of herpes zoster, suggesting a complex interaction between genetic predisposition, immunological senescence, and environmental influences in the pathophysiology of VZV reactivation. [1]
Host Immune Recognition and Antigen Presentation
Varicella zoster virus (VZV) seropositivity is significantly influenced by genetic factors within the Major Histocompatibility Complex (MHC) region, which are crucial for initiating adaptive immune responses. Specific genetic variants in genes like HLA-DQB1 are associated with the antibody response to VZV glycoproteins E and I, indicating their role in presenting viral antigens to immune cells. [2] The broader HLA region, encompassing genes such as HLA-DQA1, HLA-DRB6, and HLA-DRB1, encodes proteins that bind and display peptide fragments of the virus on the cell surface. This antigen presentation is a fundamental form of receptor activation, directly impacting how effectively the host's T cells recognize infected cells and mobilize an antiviral response. [2] The specific HLA alleles an individual possesses can determine the repertoire of viral peptides that can be presented, thereby shaping the strength and nature of the ensuing antibody-mediated immunity and contributing to the establishment of VZV seropositivity.
Intracellular Signaling and Gene Regulation in Viral Response
Following the initial recognition of VZV antigens, a sophisticated network of intracellular signaling cascades is activated, governing the host's defense mechanisms. Pathways such as cell surface receptor-linked signal transduction and G-protein coupled receptor (GPCR) signaling are vital for relaying external signals from antigen-presenting cells into the nucleus. [8] These cascades often lead to the activation or repression of specific transcription factors, which then regulate the expression of target genes essential for antiviral activity, including those involved in immune cell proliferation, differentiation, and the production of antiviral cytokines and antibodies. Genetic variations can influence the efficiency or specificity of these signaling pathways and transcription factor activities, thereby modulating the overall magnitude and duration of the host's immune response to VZV and influencing the likelihood of achieving seropositivity. [2]
Metabolic Reprogramming and Cellular Defense
Viral infections, including VZV, induce substantial metabolic alterations within host cells to meet the energy demands of both viral replication and the host's robust immune response. Core metabolic pathways, such as the citric acid cycle (TCA cycle) and respiratory electron transport, are critical for generating ATP, which powers immune cell functions like proliferation and antibody synthesis. [8] Host cells strategically modify their biosynthesis and catabolism processes, for example, by altering lipid or amino acid metabolism, to either impede viral propagation or enhance the functionality of immune cells. The tight regulation of these metabolic pathways, including flux control, represents a crucial aspect of the host's defense strategy, influencing the ability to mount an effective response against VZV and ultimately impacting the establishment and maintenance of seropositivity. [8]
Systems-Level Immune Orchestration and Clinical Implications
The host's defense against VZV involves a highly integrated system of interacting pathways and cellular processes, characterized by extensive pathway crosstalk and hierarchical regulation. For instance, signaling pathways like PI3K/Akt and FGFRs, observed in other infectious contexts, likely interact with antigen presentation mechanisms to fine-tune the antiviral response and ensure effective immune cell activation. [8] This complex systems-level integration ensures a coordinated and multifaceted defense, leading to emergent properties such as immunological memory and sustained VZV seropositivity. [2] Identifying instances of pathway dysregulation, such as through molecular mimicry, or understanding compensatory mechanisms that maintain immune homeostasis, is essential for uncovering potential therapeutic targets. [9] Insights into these intricate host-pathogen interactions are directly applicable to the development of improved vaccination strategies and immunotherapies, aiming to prevent VZV infection or mitigate its clinical manifestations. [2]
Genetic and Host Factors in VZV Immunity
Genetic variants within the Major Histocompatibility Complex (MHC) region, specifically HLA-DQB1 and HLA-DQA1, have been identified as determinants of varicella zoster virus (VZV) seropositivity. [2] These genetic associations suggest an underlying host genetic influence on the ability to mount an antibody-mediated immune response to VZV, impacting both initial seropositivity and potentially the long-term maintenance of immunity. Understanding these genetic predispositions can contribute to personalized medicine approaches by identifying individuals with distinct immune response profiles. Beyond genetics, host demographic factors such as age and sex are significant predictors of humoral immune responses to common pathogens, including VZV. [6] Studies indicate a significant interaction between age and sex in determining the odds of seropositivity for various antigens, with women often exhibiting a higher rate of positivity for several serological phenotypes. [6] These non-genetic variables are critical considerations in assessing an individual's immune status and susceptibility to VZV infection and reactivation, informing risk stratification and potential intervention strategies.
Risk Assessment and Prognostic Implications of VZV Reactivation
VZV seropositivity, particularly indicating prior chickenpox infection, carries the long-term prognostic implication of potential reactivation as herpes zoster. The incidence of herpes zoster is substantial and increasing, leading to significant morbidity, with up to 3% of cases requiring hospitalization annually. [4] Identifying individuals at high risk for herpes zoster, such as those with older age, female sex, specific ancestries, or a family history, is crucial for proactive patient management. Furthermore, VZV reactivation has been associated with serious comorbidities and long-term complications beyond the acute vesicular rash. Research indicates that herpes zoster is a risk factor for cerebrovascular disease and myocardial infarction, highlighting its systemic implications. [4] Immunosuppression, whether due to disease or medication, is a major risk factor for reactivation, underscoring the need for careful monitoring and preventive measures in vulnerable populations. Genetic variations in the HLA region are also associated with susceptibility and age of onset for herpes zoster, offering targets for more refined risk stratification. [4]
Clinical Utility of Serological Testing and Prevention Strategies
Serological testing for VZV antibodies serves as a diagnostic utility to determine prior exposure and immune status, which is fundamental for risk assessment, especially in populations born before the widespread availability of the varicella vaccine. However, interpreting serological test results requires caution, as negative results could imply no prior contact, an inability to mount an antibody response, or antibodies not being a good proxy for immune status. [2] Conversely, positive titers might reflect cross-reactivity or antibody levels that fluctuate over time due to various host and environmental factors. [2] Despite these diagnostic nuances, understanding VZV seropositivity is integral to guiding prevention strategies, particularly through vaccination. While the herpes zoster vaccine is recommended for individuals aged 60 years and older, its effectiveness is approximately 50% and it remains under-utilized. [4] Targeted vaccination campaigns and improved uptake, informed by individual risk profiles and serological status, are vital to reduce the burden of herpes zoster and its associated complications, contributing to improved public health outcomes.
Frequently Asked Questions About Varicella Zoster Virus Seropositivity
These questions address the most important and specific aspects of varicella zoster virus seropositivity based on current genetic research.
1. My friend got shingles, but I had chickenpox too. Why haven't I?
Your genetic makeup likely plays a significant role in your susceptibility to shingles, even if you both had chickenpox. Variations in genes within your Major Histocompatibility Complex (MHC) region, like HLA-B, can influence how your immune system controls the latent virus, affecting your personal risk of reactivation. This means some individuals are genetically more prone to shingles than others.
2. If my parents had shingles, am I more likely to get it?
Yes, there can be a genetic component to shingles susceptibility that runs in families. Genes within the MHC region, such as HLA-DQA1, HLA-DRB6, HLA-DRB1, and HLA-DQB1, are associated with both your immune response to the virus and your risk of reactivation. These inherited genetic differences can influence viral latency and the strength of your immune response.
3. I tested positive for chickenpox antibodies. What does that mean for my future?
A positive test means you've been exposed to the varicella zoster virus before, either naturally or through vaccination, and your body has developed an immune response. While this generally protects you from getting chickenpox again, it doesn't prevent future reactivation as shingles. Your specific genetic profile can further influence your long-term immunity and risk of shingles.
4. I had chickenpox as a kid. Why could I still get shingles?
Even if you had chickenpox, the virus remains dormant in your nerve cells. Seropositivity indicates prior exposure but doesn't prevent this dormant virus from reactivating as shingles later in life. Genetic factors, particularly in your MHC region, affect how well your immune system keeps the virus suppressed, influencing your risk of reactivation.
5. Does my family's background affect my chickenpox or shingles risk?
Yes, your ancestral background can play a role. Genetic studies have primarily focused on specific populations, like White British individuals, and the genetic determinants identified may not be the same or have the same effect in other diverse groups. This means your unique genetic heritage could influence your immune response and susceptibility to both primary infection and reactivation.
6. Why did my sibling get a milder chickenpox than I did?
The severity of chickenpox can be influenced by individual genetic differences in immune response. Variants within your Major Histocompatibility Complex (MHC) region, including genes like HLA-DQA1, HLA-DRB6, and HLA-DRB1, affect the strength and nature of your immune system's reaction to the virus. These genetic factors can lead to varying clinical manifestations, even among siblings.
7. Could a genetics test predict my personal shingles risk?
Research is identifying specific genetic variants, particularly in your MHC region, that are associated with VZV immune responses and susceptibility to herpes zoster. While not yet routine, genetic studies can inform personalized risk assessments for shingles. This could eventually guide targeted preventive or therapeutic strategies based on your unique genetic profile.
8. Why might my chickenpox antibody levels change over time?
Your antibody levels against the varicella zoster virus can naturally fluctuate over time due to various host and environmental factors. This makes consistent and accurate measurement challenging. While antibodies are crucial for long-term immunity, their levels aren't always a precise indicator of past contact or current immune status.
9. Why don't we fully understand all the reasons why some people get shingles?
Our understanding of shingles risk is still developing because current research doesn't fully account for all factors. Beyond identified genetic variations, the intricate interplay of environmental exposures and gene-environment interactions also influences your immune response to the virus. This contributes to what's called "missing heritability," meaning there are still unknown genetic and non-genetic factors at play.
10. Does my daily stress or diet affect my shingles risk?
While specific details on diet or stress for VZV are not fully outlined in current research, it is acknowledged that environmental exposures and gene-environment interactions influence immune responses. These external factors can certainly play a role in modulating your immune system, potentially impacting the dormant virus and your risk of shingles reactivation.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
[1] Crosslin, D. R., et al. "Genetic variation in the HLA region is associated with susceptibility to herpes zoster." Genes & Immunity, vol. 16, no. 8, 2015, pp. 544–550.
[2] Butler-Laporte G. "Genetic Determinants of Antibody-Mediated Immune Responses to Infectious Diseases Agents: A Genome-Wide and HLA Association Study." Open Forum Infect Dis, 2020.
[3] Stanaway, I. B. et al. "The eMERGE genotype set of 83,717 subjects imputed to ~40 million variants genome wide and association with the herpes zoster medical record phenotype." Genet Epidemiol. 2018.
[4] Crosslin DR. "Genetic variation in the HLA region is associated with susceptibility to herpes zoster." Genes Immun, 2014.
[5] Sallah, N. et al. "Distinct genetic architectures and environmental factors associate with host response to the γ2-herpesvirus infections." Nat Commun. 2020.
[6] Scepanovic P. "Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines." Genome Med, 2018.
[7] Rubicz, R. et al. Genome-wide genetic investigation of serological measures of common infections. Eur J Hum Genet, 2015.
[8] Roberts CH, et al. "Pathway-Wide Genetic Risks in Chlamydial Infections Overlap between Tissue Tropisms: A Genome-Wide Association Scan." Mediators Inflamm, 2017.
[9] Cusick MF, Libbey JE, Fujinami RS. "Molecular mimicry as a mechanism of autoimmune disease." Clin Rev Allergy Immunol, 2012; 42:102–11.