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:
- http://osp.od.nih.gov/sites/default/files/EFS-ADA_RAC120209.pdf
- http://www.childrenshospital.org
- 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
- http://www.jci.org/articles/view/41305
- http://www.chw.org/medical-care/endocrine/endocrine-conditions/disorders-affecting-calcium-metabolism/digeorge-syndrome
- https://www.orpha.net/data/patho/Pro/en/Agammaglobulinemia-FRenPro10310.pdf
- http://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/agammaglobulinemia-x-linked-autosomal-recessive
- http://www.techtimes.com/articles/89555/20150930/eli-lilly-incyte-announce-baracitinib-superior-to-methotrexate-in-alleviating-rheumatoid-arthritis.htm
- http://www.anaphore.com/News/092215.htm
- 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
- http://www.arthritis.org/about-arthritis/types/rheumatoid-arthritis/treatment.php
