Immune disorders

Immune system malfunction results in 3 types of immune disorders: Autoimmune disorders, immunodeficiency disorders and allergies.

• Autoimmune disorders occur when immune system becomes self-destructive i.e. it attacks its own healthy tissues/cells, e.g. rheumatoid arthritis, diabetes. According to American Autoimmune Related Diseases Association (AARDA) about 5-10% of US population suffers from autoimmune disorders.
• Immunodeficiency weakens the immune system so that it is unable to produce antibodies and cannot fight against infections and diseases, e.g. SCID, Di-George Syndrome (DGS) etc.
• Allergies are result of immune system's reaction with external substances called allergens such as pollen, certain food, pet dander etc. When immune system overreacts with the allergen it produces antibody IgE that triggers the release of histamine which causes the allergy symptoms (such as runny nose, itching/hives, fever, swelling/edema, vomiting etc.). Allergens are mostly harmless and most people are not allergen sensitive. Allergies can cause certain specific conditions such as eczema, sinus problem, and asthma. In some cases allergies can be life threatening such as anaphylaxis (caused by insect venom or certain food such as peanut and some type of medications).

Following are some immune system disorders:

SCID (Severe Combined Immunodeficiency) or Bubble boy syndrome: It is a genetic primary immunodeficiency which is characterized by defect of both B cell and T cell, and thus named as combined immunodeficiency. Among the 14 types of SCID the most common are XSCID (about 45% of cases) and ADASCID (about 15% of cases).

In XSCID or X linked SCID there is mutation in IL2-RG/CD132 gene (that codes common gamma chain protein which promotes the growth of T cells, B cells, NK cells) on X chromosome(X13) which mostly affects the male child as male has only one X chromosome(XY) in comparison with female(XX). As IL2RG gene is responsible for growth and maturation of T/B lymphocytes, mutation in this gene results in very low production of T cells, NK cells and causes defective/non-functional B cells. Symptoms of XSCID include very low level of IgG, pneumonitis, ear infection, failure to gain weight and to grow normally. The most effective treatments include bone marrow transplantation, intravenous immunoglobulin G therapy, and very recently discovered Gene-Transduced Autologous CD34+ Stem Cell therapy (phase 1 clinical trial) [1].

ADASCID results from the mutation in the gene on chromosome20 (autosome) that encodes the enzyme adenosine deaminase (ADA) which is essential for metabolic function of T cells. ADA helps eliminate deoxyadenosine, which is generated when DNA is broken down. So mutation in ADA results in precipitation of deoxyadenosine that is very toxic to lymphocyte. Symptoms include neurological problems, pneumonia, chronic diarrhea, and widespread skin rashes that affect both male and female child. Treatment includes BMT and gene therapy. Recent research in Boston Children’s Hospital applied gene therapy by reprogramming a patient’s immune system by viral vector transduction. In this method the patient’s abnormal bone marrow cells are interchanged with the functional version of the gene [2]. But patients have risk of having leukemia because the inserted DNA can be interfering with the normal functional gene.

Omenn syndrome: Another immunodeficiency (a type of SCID) results from missense mutations in recombinase activating genes RAG-1 and RAG-2 (on chromosome11) [3]. RAG-1 and RAG-2 are essential for gene recombination and generation of TCR and BCR. So a patient with this syndrome does not have B cells, but have auto reactive oligoclonal T cells [4]. Symptoms include skin inflammation in the form of red rashes (erythroderma), chronic diarrhea, lymphadenopathy, eosinophilia, poor growth and infections. Treatments include BMT but life expectancy is very low.

DiGeorge syndrome: It is a congenital primary immunodeficiency named after Dr Angelo DiGeorge. In this syndrome thymus and parathyroid gland are absent or abnormal, that results in T cell deficiency and low calcium level in blood. Also in this syndrome there is an autosomal mutation in chromosome 22q11.2, thus it is also known as 22q11.2/DGCR deletion syndrome [5]. Symptoms include congenital heart disease, defective immune system, cleft palate etc. This syndrome is diagnosed by FISH (Fluorescent In Situ Hybridization) blood test. No effective treatment is there for this disease.

Agammaglobulinemia: This can be of two types - X linked/Sex Linked (XLA) and Autosomal Recessive (ARA). It is a genetic immune disorder that is represented by very low level of immunoglobulin antibody due to genetic defect in B cells. In XLA (mainly affects male child as they have only one X chromosome) there is a mutation in Btk (Bruton’s Tyrosine Kinase) gene present in X chromosome that is responsible for B cell development and maturation. ARA is inherited as autosomal recessive trait and the patient does not have any circulating mature B cells as there is mutation in pre-B cell receptor [6]. The genes involved in ARA are µ heavy chain of IgM antibody, Igα chain, Igβ chain and an adaptor protein BLNK [7]. Diagnosis is done by serum immunoglobulin test and DNA analysis. Treatment includes intravenous and subcutaneous immunoglobulin (IgG) injection but this is not a permanent cure.

Rheumatoid Arthritis (RA): It is a chronic autoimmune disorder (when immune system attacks body’s own healthy tissues) that affects the joints and results in pain, stiffness (mainly in the morning), swelling and loss of function of joints. There is no known cause and no permanent cure of RA and women are more prone to this disorder. 1% of world population is affected by RA. Lifestyle changes, diet, aerobic exercise, yoga and certain medications can ease the RA symptoms. Medications include NSAIDs (Non Steroidal Anti-Inflammatory Drug) such as ibuprofen, celecoxib (a Cox2 inhibitor that is relatively safe for the stomach), corticosteroids such as prednisone, DMARDs (Disease Modifying Anti-Rheumatic Drug) such as methotrexate or baricitinib [8], sulfasalazine, Jak inhibitor (newest) such as tofacitinib and biologics drug (that are injectable and infusional) such as abatacept, anakinra etc. But all of these medications have serious side effects and so need to be taken only in very low doses and not for extended periods of time. A biopharmaceutical company (RuiYi) recently announced human dosing of a therapeutic antibody named Gerilimzumab (which is under clinical trial now) that targets cytokine IL-6 to treat RA [9]. Another very recent discovery includes cytokine IL27 as a regulator of inflammation in lymphoid rich RA, that was published in Journal of Experimental Medicine [10]. Recent studies found that some of RA drugs can increase the death risk of the patient. Recent research suggests that some genes such as HLA, STAT4 (which regulate and activate immune system), TRAF1&C5 (involved in chronic inflammation) and PTPN22 (involved in development and progression of RA), and inflammation on synovium (joint tissue lining) that cause cartilage damage are mainly responsible for RA [11]. Some specific tests such as rheumatoid factor antibody test, anti CCP (Cyclic Citrullinated Peptide) test, C reactive protein (CRP) test, Erythrocyte Sedimentation Rate (ESR) test could diagnose RA.

Sjogren's syndrome: It is chronic autoimmune disorder named after Dr Henrick Sjogren, where white blood cells attack body’s moisture producing glands such as saliva gland. Mostly women above 40 years age are affected by this disease and currently 4 million Americans are affected. The most common symptoms are dry eye, dry mouth, fatigue, and joint pain. This disease can also affect the kidney, lungs, pancreas, gastrointestinal system and CNS. Currently there is no cure for this disease.

Other than the above mentioned diseases there are various other types of immune system disorders including cancer of immune system cells i.e. B lymphocytes and T lymphocytes (lymphoma) and organs such as lymph nodes, spleen etc. One post is too short to describe all of them. I will try to explain some of them in future.

References:

1. http://osp.od.nih.gov/sites/default/files/EFS-ADA_RAC120209.pdf
2. http://www.childrenshospital.org
3. http://www.researchgate.net/profile/Tayfun_Guengoer2/publication/46628483_Identical_mutations_in_RAG1_or_RAG2_genes_leading_to_defective_V(D)J_recombinase_activity_can_cause_either_T-B-_severe_combined_immune_deficiency_or_Omenn_syndrome/links/02e7e523bea3435c50000000.pdf
4. http://www.jci.org/articles/view/41305
5. http://www.chw.org/medical-care/endocrine/endocrine-conditions/disorders-affecting-calcium-metabolism/digeorge-syndrome
6. https://www.orpha.net/data/patho/Pro/en/Agammaglobulinemia-FRenPro10310.pdf
7. http://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/agammaglobulinemia-x-linked-autosomal-recessive
8. http://www.techtimes.com/articles/89555/20150930/eli-lilly-incyte-announce-baracitinib-superior-to-methotrexate-in-alleviating-rheumatoid-arthritis.htm
9. http://www.anaphore.com/News/092215.htm
10. Gareth W. Jones et al., Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis, Journal of Experimental Medicine, Sept 28, 2015, http://jem.rupress.org/content/early/2015/09/22/jem.20132307.abstract
11. http://www.arthritis.org/about-arthritis/types/rheumatoid-arthritis/treatment.php