Integration Of Genetics And The Transcriptome Of Psoriasis
To learn the potential functional implications of the SNPs uncovered in this meta-GWAS , we evaluated whether positional candidate genes around each SNP had altered gene expression in psoriasis. Many studies have examined the transcriptome of psoriasis, which is defined as differentially expressed genes between lesional and nonlesional skin. Recently, our group conducted a meta-analysis-derived transcriptome of all the published studies using HGU133 Plus 2.0 chips, called MAD3 transcriptome, defining a robust list of psoriasis DEGs . shows a Manhattan-type plot depicting the gene expression fold change on the MAD3 transcriptome ordered by their position on the genome . Genes located +/ 500 kb around each of 36 psoriasis SNPs identified in the meta-GWAS are highlighted in colors . The subset of these positional genes that were DEGs in the MAD3 transcriptome are represented as dots of darker shades and listed on the right-hand side . The notable genes IL23R, IL12B, IL23A, and IL4 were added because there were SNPs in these genes, and although they were not detected by microarray, they were determined by RT-PCR or FACS to be differentially regulated . Thus, many genetic susceptibility loci also contain genes with strong upregulation of mRNA products. It is interesting and logical that the Th2 cytokine IL-4 is the only gene downregulated .
Problems With The Immune System
Your immune system is your body’s defence against disease and it helps fight infection. One of the main types of cell used by the immune system is called a T-cell.
T-cells normally travel through the body to detect and fight invading germs, such as bacteria. But in people with psoriasis, they start to attack healthy skin cells by mistake.
This causes the deepest layer of skin to produce new skin cells more quickly than usual, triggering the immune system to produce more T-cells.
It’s not known what exactly causes this problem with the immune system, although certain genes and environmental triggers may play a role.
The Other Side: Antigen Presentation By Hla Molecules In Psoriasis
While most, if not all, autoimmune diseases are linked with certain HLA alleles , HLA-C*06:02 is the predominant psoriasis risk gene . HLA class I molecules present short peptide antigens to TCRs of CD8+ T cells. Such antigenic peptides are usually derived within the antigen presenting cell from parent proteins by proteasomal cleavage and loaded onto HLA-class I molecules. The HLA/peptide complex is then transported to the cell membrane where it can be recognized by CD8+ T cells . Thus, HLA-class I-restricted immune responses are usually directed against target cells which produce the antigenic peptide.
HLA-C*06:02-presented non-apeptides possess anchor amino acids at residues 2 and 9 , along with a putative anchor at residue 7 . HLA-C*06:02 features very negatively charged pockets and thus binds to distinct positively charged peptides. Given that between 1,000 and 3,000 different self-peptides have been detected on HLA-C*06:02 under experimental conditions, multiple cellular proteins should be, in principle, presented by this HLA molecule and recognizable by CD8+ T cells .
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Are There Complications Of Psoriasis
In some people, psoriasis causes more than itchiness and red skin. It can lead to swollen joints and arthritis. If you have psoriasis, you may be at higher risk of:
- Use medicated shampoo for scales on your scalp.
Other steps you should take to stay as healthy as possible:
- Talk to your healthcare provider about lowering your risk for related conditions, such as heart disease, depression and diabetes.
- Lower your stress with meditation, exercise or seeing a mental health professional.
The Plot Thickens: Actual Auto
Pathogenic T cells in psoriatic skin lesions facilitate hyperproliferation of keratinocytes, influx of neutrophilic granulocytes, as well as production of other inflammatory cytokines, chemokines and antimicrobial peptides. They feature a Th17 signature, i.e., they express IL-17A, IL-22, and IFN- . Dendritic cells maintain activation and differentiation of lesional Th17 cells primarily through secretion of IL-23 .
Figure 2. Initiation of psoriasis by antigen-dependent and antigen-independent immune mechanisms. Complexes of self-DNA with fragments of the antimicrobial peptide, cathelicidin, can stimulate plasmacytoid dendritic cells through TLR9. They can also be presented by HLA-C*06:02 molecules and specifically activate T cells through their TCR. Likewise, the melanocyte-derived ADAMTSL5 can activate pathogenic CD8+ T cells after presentation by HLA-C*06:02.
In general, both HLA restriction and peptide specificity of a given T cell are determined by its T cell receptor repertoire . Activation and clonal expansion of T cells occur upon antigenic stimulation. In the absence of foreign antigens, clonal T cell expansion is highly suggestive for autoimmunity in inflammatory diseases . Indeed, oligoclonal T cell expansion has been identified in psoriatic lesions in early well-designed studies as well as in more recent investigations . It has been interpreted as an indicator for antigen-specific immune responses.
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Why Is Psoriasis An Autoimmune Disorder
As part of its defense against foreign invaders, your body makes specialized white blood cells called T-cells. Under normal circumstances, T-cells identify and coordinate attacks on foreign invaders.
However, when you have psoriasis, your T-cells mistakenly identify your skin cells as invaders and attack them. This attack injures the skin cells, setting off a cascade of responses in your immune system and in your skin, resulting in the skin damage seen in psoriasis swelling, reddening, and scaling.
In an effort to heal, your skin cells begin reproducing much more rapidly than normal, and large numbers of new skin cells push their way to the surface of your skin. This occurs so quickly that older skin cells and white blood cells aren’t shed quickly enough. These discarded cells pile up on the surface of the skin, creating thick, red plaques with silvery scales on their surface: the hallmark of the classic form of plaque psoriasis.
Other Psoriasis Susceptibility Loci
The human genome is inherited in blocks, with linkage disequilibrium of genes in close proximity being inherited together. At least 12 major psoriasis susceptibility loci have now been identified, originally by linkage disequilibrium in family-based studies. Often, several candidate genes at each PSORS locus may be contributing to the disease. In the future, the gene at each locus will ultimately be identified by deep sequencing at each chromosomal position.
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Contribution Of Resident Skin Cells To Immunological Processes In Psoriasis
Multiple genetic and environmental factors influence the immunopathology of psoriasis . The mechanisms leading to the first occurrence of psoriasis in predisposed individuals are only partly known. Infections with streptococci, medications such as lithium, antimalarials, or ß-blockers, or physical or chemical stress may trigger the disease. Minimal trauma can induce rapid immigration and activation of immune cells including T-cells and neutrophils , the so-called Köbner phenomenon . Feedback loops between adaptive immune cells , innate immune cells , and resident skin cells result in an amplification and chronification of the inflammatory response. Aspects of systemic inflammation in patients with severe psoriasis are thought to contribute to comorbid diseases .
Several other skin-derived alarmins such as S100 proteins are inflammatory AMPs also implicated in the pathogenesis of psoriasis. Indeed, IL-17A induces the production of S100A7 and S100A15 by keratinocytes . Likewise, myeloid cells and keratinocytes produce the calgranulins, S100A8 and S100A9 , both of which induce T-cell mediated autoimmune reactions and inflammatory changes in keratinocytes . Similar to LL37, human ß-defensin 2 and HBD4 bind DNA, trigger TLR9 and stimulate pDC . Innate immune sensing is also facilitated by IL-26 bound to self-DNA .
Psoriasis Can Affect Internal Organs As Well As The Skin
Not only can psoriasis affect the skin, but it can have devastating effects that can affect your internal organs.
The systemic inflammation inside the body that accompanies the disease is often overlooked.
Patients may think that they are having success with their treatments if they cannot see the thick psoriasis plaques on their skin.
However, patients can have serious consequences on their joints, arteries and other organs if not properly treated early to decrease the inflammation.
It is important to know that psoriasis is an autoimmune disease. It is not contagious and is caused when the immune system attacks the skin.
As a result, scaly red patches or plaques occur on the skin.
In addition to skin problems, some patients can develop psoriatic arthritis. Signs and symptoms of this are painful, stiff and swollen joints that can come and go.
Psoriatic arthritis can affect any joint in the body, including the back or neck.
An early and accurate diagnosis of psoriatic arthritis is essential because persistent inflammation can cause damage to the joints.
Nobody knows exactly what causes psoriatic arthritis, but it can affect anyone.
Psoriatic arthritis typically occurs in people with skin psoriasis, but it can occur in people without skin psoriasis, particularly in those who have relatives with psoriasis.
Sometimes certain heart medications like B-blockers can cause a psoriasis flare on the skin or it may be triggered by a streptococcal throat infection.
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Monocytes Macrophages And Myeloid
Monocytes
Monocytes are known precursors for DCs and macrophages and as such, they have been described to be important cellular contributors to psoriatic pathology. It has been suggested that psoriatic monocytes engulf low density lipoprotein leading to overproduction of inflammatory cytokines. Additionally, psoriatic monocytes have also been described to possess increased phagocytic capabilities due to an imbalance in the ratio of cAMP/cGMP found in lesional skin. More recently an increase in CD14+ CD16+ intermediate monocytes termed Mon2 has been described in a cohort of human psoriatic patients., Interestingly, Mon2 monocytes also have been shown to be linked to an increased risk of CVD and to be predictive of myocardial infarction and death.
Macrophages
Myeloid-derived suppressor cells
A1b1 Integrin And Epidermal T Cell Accumulation
Based on the findings that expansion of skin resident T cells is important in psoriasis development in the xenotransplantation AGR mouse model, the role of tissue-specific factors in activation and expansion of resident T cells has been further explored 66. T cells need to pass through the dermo-epidermal junction in order to enter the epidermis and collagen fibrils are an essential part of the dermo-epidermal junction. The most important basement membrane collagen is collagen IV. Long-term activation of T cells results in the expression of a receptor for collagen IV, the heterodimeric integrin a1b1 . It has been shown that epidermal accumulation of a1b1-positive Th1 and Tc1 cells correlate with psoriasis development. Blocking a1b1 with a neutralizing monoclonal antibody prevents epidermal T cell accumulation and subsequent psoriasis development in the xenotransplantation AGR mouse model. a1b1 expression may act as a checkpoint for entry of T cells into epidermis with a1b1-positive epidermal T cells potentially playing an important role in psoriatic lesion formation. Hence targeting of these integrins may offer new therapeutic approaches in psoriasis and possibly in other autoimmune disease.
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How Does The Immune System Work
Your immune system is supposed to protect against infection and diseases through inflammation. It does this by sending immune cells and blood to parts of the body it feels are threatened. For example, if you fall and scrape your elbow, it will swell and become red as your immune systems inflammatory response works to heal the injury.
The immune system works with both your circulatory and lymphatic systems. This involves the transportation of antigens and pathogens to lymph nodes and/or the spleen for processing and eradication. Immune cells, including phagocytes and neutrophils, circulate through the circulatory system to the location of the pathogenseither in the lymph nodes or spleento overwhelm and destroy foreign invaders.
The immune system works to eradicate pathogens with help from the integumentary system. The integumentary system is made up of all the skin cells of the body. Both the skin and the immune system work together to keep foreign pathogens out of the body. Interestingly, the skin is the first line of defense because it acts as a barrier to the inner body.
Skin: Hormones Target And Synthesis Organ
The skin, the central nervous system and the endocrine system have a common embryological origin and they all express the same, numerous mediators . For example, human skin produces, activates or inactivates neuropeptides like serotonin some opioid peptides and their receptors are also expressed in the skin .
The normal skin development and function is influenced by hormones: for example, the growth hormone stimulates keratinocyte proliferation , and thyroid hormones act directly on hair follicles . The skin is a neuroendocrine organ, capable of hormone synthesis and release : corticosteroids and sex hormones are synthesized and transformed catecholamines are synthesized by keratinocytes and melanocytes .
Dermal fibroblasts present strong circadian rhythm and melatonin is implicated in the regulation of hair growth cycle and is metabolized . Prolactin is also implicated in hair growth regulation, and scalp skin and hair follicles are sources of prolactin .
The cutaneous endocrine system is highly important in multiple systemic diseases .
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Why Do People Get Psoriasis
Both genetic and environmental factors are believed to be responsible for whether or not a person will get psoriasis. The theory is that those who develop the disease are born with a particular genetic makeup that causes vulnerability to psoriasis, and those who actually develop the disease are exposed to something in the environment that triggers the disorder.
Encountering certain environmental triggers seems to jump-start the machinery of the body’s immune system in vulnerable individuals. Some of the environmental factors that seem to be able to trigger psoriasis or to cause a flare-up of the condition in someone who already has the disorder include:
- Infections. Psoriasis often starts or worsens after you’ve had some kind of infection, especially one caused by streptococcus bacteria .
- Medications. Lithium, anti-malaria drugs, high blood pressure medicines and the anti-inflammatory drug Indocin are some of the drugs that seem to be possible triggers.
- Skin injury. Overly dry skin, sunburn, cuts, and scratches sometimes lead to psoriasis.
- Stress. Some studies suggest that stress can serve as a trigger for psoriasis.
Clinical And Histological Features Of Psoriasis
Psoriasis is a common skin disease affecting 13% of the North American population. Classic psoriasis, called large plaque psoriasis or psoriasis vulgaris, is the most common type. It can be fairly easily diagnosed as characteristic red colored plaques with well-defined borders and silvery-white dry scale, located on elbows, knees, and scalp and in the lumbosacral area , although it can be more extensive . Other less common types of psoriasis also occur, such as guttate, inverse, pustular, erythrodermic, palmo-plantar, and drug-associated psoriasis .
The amount of psoriasis covering the body can be measured roughly as a percentage of body area, using the palm to represent 1% of the body. In approximately one-third of patients, more than 10% of the body is covered, and this is termed moderate to severe psoriasis. Clinical disease can also be assessed by a trained health-care practitioner, using the Psoriasis Activity and Severity Index score. This tool ranks severity and area of erythema , induration , and desquamation of the plaques in different body sections, with 72 as the maximal score. A baseline PASI score is assigned , the score is then reevaluated at various time points, and the improvement is calculated. Most clinical studies consider that an improvement of 75% from baseline is required for the treatment to be considered successful , although a PASI50 can also be very meaningful for an individual patient.
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Shades Of Gray: Crosstalk Between Adaptive And Innate Immunity In Psoriasis
In addition to the antigen-specific facilitation of inflammation in psoriasis, there are several strong connections to components of the innate immune system. The crosstalk between the innate and adaptive branches of the immune system in psoriasis is complex and can only be highlighted by a few selected examples. Its fine-tuning arguably determines the actual clinical correlate within the spectrum of the disease. Indeed, there is accumulating circumstantial evidence that in patients with stable and mild disease, mechanisms of adaptive immunity are more likely to be in the foreground, while innate mechanisms seem to be more important in patients with active severe disease, systemic involvement and comorbid conditions . The impact on systemic comorbid diseases has been interpreted, at least in part, as a systemic spillover of innate inflammatory processes in severe psoriasis . Of course, such factors are not specific for psoriasis, but appear to account for a general inflammatory state in patients with severe psoriasis.
Patients with severe psoriasis have increased levels of inflammatory cytokines, CRP, fibrinogen, 2 macroglobulin or PAI-1 in the blood , they show transcriptomic, proteomic and metabolomic abnormalities and there are connections with chronic stress and biophysical properties of the skin .
Genetic Background Of Psoriasis And Its Relationship To Immune Function
Investigators have long appreciated the genetic nature of psoriasis. The concordance rate of psoriasis is approximately 70% in monogenic twins and 20% in dizygotic twins, depending on the study and the population . Approximately three billion base pairs exist in the human genome, and only 35% of these sequences code for proteins. A disease-causing mutation is usually quite rare and is commonly found in a coding or regulatory region. Psoriasis is a complex disease with over 30 single nucleotide polymorphisms contributing to disease risk, but two gene mutations have recently been found that can independently induce psoriasis , and these genes have an effect on both the skin and the immune system.
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What Is An Autoimmune Disorder
Your body’s immune system is responsible for fighting foreign invaders threatening your health: bacteria, viruses, and fungi are just a few examples. Your good health depends partly on two important features of the immune system:
Unfortunately, when you have an autoimmune disease, your body’s immune system mistakenly confuses what is “self” with what is “other.” Instead of protecting your body, the immune system produces cells and chemicals that attack your own body, causing damage and disease.
There are many different autoimmune diseases, including psoriasis, rheumatoid arthritis, some types of thyroid diseases, some forms of anemia, lupus, celiac disease, and type 1 diabetes.