Granzyme B (GrB) is one of the

serine protease Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Serin ...

granzymes most commonly found in the granules of

natural killer cells Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cells ...

(NK cells) and cytotoxic T cells. It is secreted by these cells along with the pore forming protein

perforin Perforin-1 Perforin (PRF), encoded by the PRF1 gene, is a pore-forming toxic protein housed in the secretory granules of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Together, these cells are known as cytotoxic lymphocytes (CLs). ...

to mediate

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

in target cells. Granzyme B has also been found to be produced by a wide range of non-cytotoxic cells ranging from

basophils Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. They are the largest type of granulocyte. They are responsible for inflammatory reactio ...

and

mast cells A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a ...

smooth muscle cells Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal muscle, skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non-striated ...

. The secondary functions of granzyme B are also numerous. Granzyme B has shown to be involved in inducing

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

by stimulating

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

release and is also involved in

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...

remodelling. Elevated levels of granzyme B are also implicated in a number of

autoimmune diseases An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated that ...

, several skin diseases, and

type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that occurs when the body's immune system destroys pancreatic cells (beta cells). In healthy persons, beta cells produce insulin. Insulin is a hormone require ...

Structure

In humans, granzyme B is encoded by ''GZMB'' on chromosome 14q.11.2, which is 3.2kb long and consists of 5

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence i ...

. It is one of the most abundant granzymes of which there are 5 in humans and 10 in mice. Granzyme B is thought to have evolved from a granzyme H related precursor and is more effective at lower concentrations than the other granzymes. The enzyme is initially in an inactive precursor

zymogen In biochemistry, a zymogen (), also called a proenzyme (), is an inactive precursor of an enzyme. A zymogen requires a biochemical change (such as a hydrolysis reaction revealing the active site, or changing the configuration to reveal the activ ...

form, with an additional amino terminal peptide sequence. This sequence can be cleaved by

cathepsin C Cathepsin C (CTSC) also known as dipeptidyl peptidase I (DPP-I) is a lysosomal exo-cysteine protease belonging to the peptidase C1 protein family, a subgroup of the cysteine cathepsins. In humans, it is encoded by the ''CTSC'' gene. Function ...

, removing 2

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

. Cathepsin H has also been reported to activate granzyme B. Granzyme B's structure consists of two six-stranded

β sheets The beta sheet (β-sheet, also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gene ...

with three trans domain segments. In the granules of cytotoxic lymphocytes the enzyme can exist in two

glycosylated Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...

forms. The high mannose form weighs 32kDa and the complex form, 35kDa. Granzyme B contains the

catalytic triad A catalytic triad is a set of three coordinated amino acid residues that can be found in the active site of some enzymes. Catalytic triads are most commonly found in hydrolase and transferase enzymes (e.g. proteases, amidases, esterases, aminoac ...

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...

aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protei ...

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

in its

active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the ''binding s ...

and preferentially cleaves after an

residue situated in the P1 position. The aspartic acid residue to be cleaved associates with an

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...

residue in the enzyme's binding pocket. Granzyme B is active at a neutral pH and is therefore inactive in the acidic CTL granules. The enzyme is also rendered inactive when bound by serglycin in the granules to avoid apoptosis triggering inside the cytotoxic T cells themselves.

Delivery

Granzyme B is released with perforin which inserts into a target cell's

plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

forming a

pore Pore may refer to: Biology Animal biology and microbiology * Sweat pore, an anatomical structure of the skin of humans (and other mammals) used for secretion of sweat * Hair follicle, an anatomical structure of the skin of humans (and other ...

. Perforin has a radius of 5.5 nm and granzyme B has a stokes radius of 2.5 nm and can therefore pass through the perforin pore into the target to be destroyed. Alternatively, once released, granzyme B can bind to negatively charged

heparan sulfate Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs in a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...

containing receptors on a target cell and become endocytosed. The

vesicles Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle In a neuron, synaptic vesicles (or neurotransmitter vesicles) s ...

that carry the enzyme inside then burst, exposing granzyme b to the

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

and its substrates. Hsp-70 has also been linked to aiding granzyme B entry. Granzyme B has also been proposed to enter a target by first exchanging its bound serglycin for negative

phospholipids Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typi ...

in a target's plasma membrane. Entry then occurs by the less selective process of absorptive pinocytosis.

Mediated apoptosis

Once inside the target cell, granzyme B can cleave and activate initiator caspases 8 and 10, and executioner caspases 3 and 7 which trigger apoptosis. Caspase 7 is the most sensitive to granzyme B and caspases 3, 8, and 10 are only cleaved to intermediate fragments and need further cleavage for full activation. Granzyme B can also cleave BID leading to BAX/ BAK oligomerisation and cytochrome c release from the

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

. Granzyme B can cleave ICAD leading to DNA fragmentation and the laddering pattern associated with apoptosis. Granzyme B has a potential of over 300 substrates and can cleave

Mcl-1 Induced myeloid leukemia cell differentiation protein Mcl-1 is a protein that in humans is encoded by the ''MCL1'' gene. Function The protein encoded by this gene belongs to the Bcl-2 family. Alternative splicing occurs at this locus and two t ...

in the

outer mitochondrial membrane A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

relieving its inhibition of

Bim Building information modeling (BIM) is an approach involving the generation and management of digital representations of the physical and functional characteristics of buildings or other physical assets and facilities. BIM is supported by vario ...

. Bim stimulates BAX/BAK oligomerisation, mitochondrial membrane permeability and apoptosis. Granzyme B can also cleave

HAX1 HCLS1-associated protein X-1 is a protein that in humans is encoded by the ''HAX1'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that ...

(Hs-1 associated protein X-1) to facilitate mitochondria polarisation. Granzyme B can also generate a cytotoxic level of mitochondrial

reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...

(ROS) to mediate cell death. The caspase independent pathways of cell death are thought to have arisen to overcome

viruses A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are found in almo ...

that can inhibit caspases and prevent apoptosis.

Targets

Nucleus

Granzyme B has many substrates located in the

nucleus Nucleus (: nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucleu ...

. Granzyme B can cleave PARP (poly ADP ribose polymerase) and DNA PK (DNA protein kinase) to disrupt DNA repair and

retroviral A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. After invading a host cell's cytoplasm, the virus uses its own reverse transcriptase e ...

DNA integration. Granzyme B can also cleave nucleophosmin, topoisomerase 1 and nucleolin to prevent viral replication. Granzyme B can cleave ICP4 from the HSV 1 virus which is an essential protein used for gene transactivation and

NUMA Numa or NUMA may refer to: * Non-uniform memory access (NUMA), in computing Places * Numa Falls, a waterfall in Kootenay National Park, Canada * 15854 Numa, a main-belt asteroid United States * Numa, Indiana * Numa, Iowa * Numa, Oklahoma * ...

(Nuclear mitotic apparatus protein) can be cleaved to prevent

mitosis Mitosis () is a part of the cell cycle in eukaryote, eukaryotic cells in which replicated chromosomes are separated into two new Cell nucleus, nuclei. Cell division by mitosis is an equational division which gives rise to genetically identic ...

. Granzyme B can also cleave DBP (DNA Binding Protein) into a 50 kDa fragment and then into an additional 60 kDa indirectly through the caspases it activates.

Extracellular matrix

Granzyme B can degrade many proteins in the

(ECM) including

fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as col ...

vitronectin Vitronectin (VTN or VN) is a glycoprotein of the hemopexin family which is synthesized and excreted by the liver, and abundantly found in serum, the extracellular matrix and bone. In humans it is encoded by the ''VTN'' gene. Vitronectin bind ...

and

aggrecan Aggrecan (ACAN), also known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan 1, is a protein that in humans is encoded by the ''ACAN'' gene. This gene is a member of the lectican ( chondroitin sulfate pr ...

. Cleavage can cause cell death by anoikis and release alarmins from the ECM inducing inflammation. Fragments of fibronectin can attract

neutrophils Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in different ...

and stimulate MMP expression from

chondrocytes Chondrocytes (, ) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word '' chondroblast'' is commonly used to describe an immatu ...

. Basophils secrete granzyme B to degrade

endothelial The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...

cell-cell contacts allowing

extravasation Extravasation is the leakage of a fluid out of its contained space into the surrounding area, especially blood or blood cells from vessels. In the case of inflammation, it refers to the movement of white blood cells through the capillary wall, ...

to sites of inflammation. Granzyme B can also induce inflammation by processing cytokines IL-1α and IL18. It can also trigger the release of IL6 and IL8 through activation of PAR1 (Protease activated receptor 1). Cleavage of vitronectin occurs at the RGD

integrin Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, o ...

binding site interrupting cell growth signalling pathways. Cleavage of

laminin Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major constituents of the basement membrane, namely the basal lamina (the protein network foundation for most cells and organs). Laminins are vital to bi ...

and fibronectin disrupts dermal-epidermal junction attachment and cross talk while decorin destruction by granzyme B causes

collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...

disorganisation, skin thinning and aging.

Keratinocytes Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes refer ...

can express granzyme B after exposure to UVA and

UVB Ultraviolet radiation, also known as simply UV, is electromagnetic radiation of wavelengths of 10–400 nanometers, shorter than that of visible light, but longer than X-rays. UV radiation is present in sunlight and constitutes about 10% of the ...

which is linked to

photoaging Photoaging or photoageing (also known as "dermatoheliosis") is a term used for the characteristic changes to skin induced by chronic Ultraviolet, UVA and UVB exposure. Effects of UV light Molecular and genetic changes UVB rays are a primary ...

of the skin. Granzyme B can also impair wound healing. Cleavage of the

von Willebrand factor Von Willebrand factor (VWF) () is a blood glycoprotein that promotes primary hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thro ...

inhibits

platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...

aggregation and of

plasminogen Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is enco ...

produces an

angiostatin Angiostatin is a naturally occurring protein found in several animal species, including humans. It is an endogenous angiogenesis inhibitor (i.e., it blocks the growth of new blood vessels). Clinical trials have been undertaken for its use in antic ...

fragment preventing

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

. The cutting of fibronectins and vitronectins delays the formation of a provisional matrix impairing wound healing further.

T cell regulation

Granzyme B is secreted by

regulatory T cells The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain immune tolerance, tolerance to self-antigens, and prevent autoimmune disease. Treg ...

(tregs) to kill

CD4 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as helper T cells, monocytes, macrophages, and dendritic c ...

⁺ T cells that have not been exposed to host cells that are restricted to the peripheral tissues and cannot reach the

thymus The thymus (: thymuses or thymi) is a specialized primary lymphoid organ of the immune system. Within the thymus, T cells mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. The thymus ...

. This activation-induced cell death (AICD) can be achieved without the Fas death pathway and prevents autoimmune reaction to self antigens.

Inhibitors

Granzyme B's most common inhibitor is SERPINB9 also known as proteinase inhibitor nine (PI-9) which is 376 amino acids long and found in the nucleus and cytoplasm. It is produced by many types of cell to protect themselves from accidental granzyme B mediated cell death. PI-9 is

metastable In chemistry and physics, metastability is an intermediate energetic state within a dynamical system other than the system's state of least energy. A ball resting in a hollow on a slope is a simple example of metastability. If the ball is onl ...

and forms an energetically favourable conformation when bound to granzyme B. The reactive loop centre (RCL) of the PI-9 molecule acts as a pseudosubstrate and initially forms a reversible Michaelis complex. Once the

peptide bond In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 (nitrogen number two) of another, along a peptide or protein cha ...

of the RCL is cleaved between positions P1 and P1', granzyme B is permanently inhibited. However, if the RCL is cleaved efficiently, PI-9 does not act as a 1:1 suicide substrate and granzyme B is left uninhibited. Granzyme M can also cleave PI-9 in the nucleus and cytoplasm to relieve granzyme B of inhibition. Protein L4-100K from

adenoviruses Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from the ...

can also inhibit granzyme B by binding at exosites and specific binding pockets. L4-100K is an assembly protein that can transport hexon capsomeres into the nucleus of an adenovirus. 100k can be cleaved to a 90kDa fragment by granzyme H to relieve this inhibition which is important in adenovirus 5 infected cells.

Role in disease

Granzyme B has a normal concentration of 20-40 pg/ml in the

blood plasma Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...

while retaining 70% activity and elevated concentrations of granzyme B are found in a number of disease states. Granzyme B can generate autoantigens by cleaving in disordered regions and linker regions of antigens exposing new

epitopes An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that binds to the epitope is called a paratope. Although ep ...

and this can cause the development of autoimmune diseases. Granzyme B release with perforin from CD8⁺ T cells can cause

heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...

and

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

transplant rejection Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipien ...

through killing of allogeneic endothelial cells. The destruction of

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

producing

β cells Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a v ...

pancreatic islets The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% o ...

is mediated by T cells and granzyme B contributing to Type 1 Diabetes. Granzyme B can also mediate the death of cells after

spinal cord injury A spinal cord injury (SCI) is damage to the spinal cord that causes temporary or permanent changes in its function. It is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Symptoms of ...

and is found at elevated levels in

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by chronic respiratory symptoms and airflow limitation. GOLD defines COPD as a heterogeneous lung condition characterized by chronic respiratory s ...

(COPD) has been attributed to granzyme B secreted from NK and T cells causing the apoptosis of bronchial epithelial cells. Matrix destabilisation and remodelling by granzyme B is also linked to

asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...

pathogenesis. Granzyme B can kill

melanocytes Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea), the inner ear, vaginal epithelium, meninges, bones, and hea ...

causing the skin condition

vitiligo Vitiligo (, ) is a chronic autoimmune disorder that causes patches of skin to lose pigment or color. The cause of vitiligo is unknown, but it may be related to immune system changes, genetic factors, stress, or sun exposure, and susceptibili ...

and granzyme B overexpression is found in

contact dermatitis Contact dermatitis is a type of acute or chronic inflammation of the skin caused by exposure to chemical or physical agents. Symptoms of contact dermatitis can include itchy or dry skin, a red rash, bumps, blisters, or swelling. These rashes ...

lichen sclerosus Lichen sclerosus (LS) is a chronic, inflammatory skin disease, of unknown cause, which can affect any body part of any person, but has a strong preference for the genitals (penis, vulva), and is also known as balanitis xerotica obliterans when i ...

and

lichen planus Lichen planus (LP) is a chronic inflammatory and autoimmune disease that affects the skin, nails, hair, and mucous membranes. It is not an actual lichen, but is named for its appearance. It is characterized by polygonal, flat-topped, violaceous p ...

cases. Cytotoxic cells expressing granzyme B have been identified close to

hair follicles The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction between ho ...

linking a possible role in hair loss. The ECM remodelling properties of granzyme B have also implicated its involvement in left ventricular remodelling, which increases the subsequent chances of

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

. The weakening of the

fibrous cap Fiber (spelled fibre in British English; from ) is a natural or artificial substance that is significantly longer than it is wide. Fibers are often used in the manufacture of other materials. The strongest engineering materials often incorp ...

of atheromatous plaques by apoptosis of smooth muscle cells has also been linked to granzyme B. More recently, a key role for extracellular granzyme B has been forwarded for a number of autoimmune (eg. arthritis, autoimmune blistering, scleroderma, lupus)(Reviewed in ) and/or age-related chronic inflammatory disorders (Photoaging, aneurysm, atherosclerosis, COPD, macular degeneration, etc)(Reviewed in Richardson et al. Granzyme B in aging and age-related pathologies. Trends Mol Med. 2024 Aug 23:S1471-4914(24)00204-1. doi: 10.1016/j.molmed.2024.07.010.). In many of these conditions, proof-of-concept has been demonstrated through the use of experimental models, genetic approaches and/or pharmacologic approaches.

References

External links

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