SCID or severe combined immunodeficiency disease is one of the most widely studied immunodeficiency diseases. Two types of severe combined immunodeficiency disease (SCID) exist with different modes of inheritance and gens involved.
Differences between the two are discussed below.
X- LINKED SCID
It is the commonest form of SCID accounting for 50-60%
Since inheritance is X-linked, it is more common in boys.
Defect is caused due to mutation in the common gamma chain subunit of cytokine receptors.
Defect in T cells are more pronounced compared to B cells. Defects in NK cell is also present
Thymus is small and devoid of lymphoid follicles and contains lobules of undifferentiated epithelial cells resembling fetal thymus.
Gene therapy has been successful.
AUTOSOMAL RECESSIVE SCID
Most common form of AR SCID Defect in T> B cells
Thymus is small and devoid of lymphoid follicles and remnants of Hassall’s corpuscles can be found.
Hematopoietic stem cell transplantation is the mainstay of treatment. Enzyme therapy and gene therapies have been tried.
SOME OTHER FORMS OF AUTOSOMAL RECESSIVE SCID
Mutations in recombinase-activating genes (RAG)
Mutations in JAK 3 have similar effects as mutations in the γc chain.
Several mutations have been described in signaling molecules associated with the T-cell antigen receptor and components of calcium channels.
Satellite DNA– A major component of centromeres is so-called satellite DNA, consisting of large arrays—up to megabases in length—of repeating sequences (from 5 bp up to 5 kb). Although classically associated with spindle apparatus attachment, satellite DNA is also important in maintaining the dense, tightly packed organization of heterochromatin.
Gene Editing and CRISPR- An exciting new development that allows high-fidelity genome editing may usher in the next era of the molecular revolution. This advance comes from a wholly unexpected source: the discovery of clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated genes (Cas), such as the Cas9 nuclease.
CHAPTER 2- ADAPTATIONS AND INJURY
Ferroptosis- Only discovered in 2012, ferroptosis is a distinct form of cell death that is triggered when excessive intracellular levels of iron or reactive oxygen species overwhelm the glutathione-dependent antioxidant defenses.
CHAPTER 3-INFLAMMATION AND REPAIR
Neutrophil extracellular traps (NETs)– NETs were mentioned in the previous edition it is further elaborated in the latest edition. Neutrophil extracellular traps (NETs) are extracellular fibrillar networks that concentrate antimicrobial substances at sites of infection and trap microbes, helping to prevent their spread.
CHAPTER 6- IMMUNITY
Rejection of tissue transplants:Elaborated compared to the previous edition.
CHAPTER 7- NEOPLASIA
A few newly added proto-oncogenes:
FMS-like tyrosine kinase 3 (FLT3) Point mutation or small duplications in Leukemia.
GTP-binding (G) proteins- GNAQ Point mutation in Uveal melanoma.
GTP-binding (G) proteins- GNAS Point mutation in Pituitary adenoma.
A few newly added tumor suppessor genes:
SDHB, SDHD (Succinate dehydrogenase complex subunits B and D TCA cycle, oxidative phosphorylation) seen in Familial paraganglioma, familial pheochromocytoma.
Elaboration of oncogenic activities of E6 an E7 proteins of human papilloma virus (HPV)
In the older edition it was mentioned that the E6 protein of HPV inactivates p53. In the 10th edition it is mentioned that in addition to inactivation of p53, E6 protein also increases telomerase expression (TERT).
Neutrophil extracellular traps (NETs) are extracellular fibrillar networks that concentrate antimicrobial substances at sites of infection and trap microbes, helping to prevent their spread. They are produced by neutrophils in response to infectious pathogens (mainly bacteria and fungi) and inflammatory mediators (e.g., chemokines, cytokines [mainly interferons], complement proteins, and ROS). The extracellular traps consist of a viscous meshwork of nuclear chromatin that binds and concentrates granule proteins such as antimicrobial peptides and enzymes. NET formation starts with ROS-dependent activation of an arginine deaminase that converts arginines to citrulline, leading to chromatin decondensation. Other enzymes that are produced in activated neutrophils, such as MPO and elastase, enter the nucleus and cause further chromatin decondensation, culminating in rupture of the nuclear envelope and release of chromatin. In this process, the nuclei of the neutrophils are lost, leading to death of the cells. NETs have also been detected in the blood during sepsis. The nuclear chromatin in the NETs, which includes histones and associated DNA, has been postulated to be a source of nuclear antigens in systemic autoimmune diseases, particularly lupus, in which individuals react against their own DNA and nucleoproteins.