TYK2

Also known as

• Tyrosine kinase 2
  
• Non-receptor tyrosine-protein kinase TYK2 
• EC 2.7.10.2
• JTK1
  

 

Physiology

Activated by:

• IFNAR2
  
• Type I interferon signalling
• Type III interferon signalling
  
• IL-6 (Interleukin 6)
• IL-10 (Interleukin 10)
• IL-12 (Interleukin 12)
• IL-23 (Interleukin 23)

Molecular actions

1. IFNAR1 (subunit 1) and IFNAR2 (subunit 2) form a cell surface receptor called IFNAR (Interferon-alpha/beta receptor).
2. IFNAR1 associates with the enzyme TYK2. 
3. IFNAR2 associates with the enzyme JAK1.

Interferon signalling

1. IFNAR1 or IFNAR2 binds an IFN to form a binary complex.
2. The interferon-subunit complex recruits the other IFNAR subunit to form a ternary complex.

JAK/STAT signalling

1. JAK1 and TYK2 are brought into close proximity and phosphorylate the 2 IFNAR subunits.
2. IFNAR recruits proteins called STATs (Signal transducer and activator of transcriptions). The STATs are activated by phosphorylation.
   
3. pSTATs form homodimers (e.g. STAT1-STAT1) or heterodimers (e.g. STAT1-STAT2). 
4. pSTAT dimers enter the cell nucleus and bind to the DNA.
5. Transcription is blocked or reduced in some target genes (repression).
6. Transcription is activated in some target genes (expression).

 

Biological functions

• Immunity
  
• Antiviral responses
• Pro-inflammatory responses

 

Clinical significance

Disorders associated with TYK2 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
• Chronic hepatitis C infection
• Immunodeficiency 35 (IMD35)
• Hyperimmunoglobulin E syndrome (HIES)
• Lymphomatoid Papulosis
• Primary cutaneous anaplastic large cell lymphoma
• Polycythemia vera

These disorders suggest an increased susceptibility to severe infections and malignancies, possibly due to cytokine signalling deficiencies. 

 

Protein profile

• Size = 1187 amino acids
• Molecular mass = 133,650 Da
• Quaternary structure: Interacts with JAKMIP1. IFNAR1 interacts with TYK2. IFNAR2 interacts with JAK1.
• Protein family = Enzyme > Tyrosine kinase > Janus kinase

 

Genetic profile

• Species: Human
• Chromosome: 19
• Band: 19p13.2
• Starts at base pair: 10,350,529
• Ends at base pair: 10,380,572 
• Sequence length (base pairs): 30,043

 

See also

• genecards.org
  
• Interferon
  

IFNAR2

Also known as

• Interferon-alpha/beta receptor beta chain
• Interferon Alpha And Beta Receptor Subunit 2
• Interferon (Alpha, Beta And Omega) Receptor 2
• Type I Interferon Receptor 2
• IFNABR

 

Physiology

IFNAR2 is activated by:

• Type I interferons
  
1. IFN-α
2. IFN-β
3. IFN-ε
4. IFN-κ 
5. IFN-ω
• Type III interferons
1. IFN-λ1
2. IFN-λ2
3. IFN-λ3
4. IFN-λ4

 

Molecular actions

1. IFNAR1 (subunit 1) and IFNAR2 (subunit 2) form a cell surface receptor called IFNAR (Interferon-alpha/beta receptor).
2. IFNAR1 associates with the enzyme TYK2. 
3. IFNAR2 associates with the enzyme JAK1.

Interferon signalling

1. IFNAR1 or IFNAR2 binds an IFN to form a binary complex.
2. The interferon-subunit complex recruits the other IFNAR subunit to form a ternary complex.

JAK/STAT signalling

1. JAK1 and TYK2 are brought into close proximity and phosphorylate the 2 IFNAR subunits.
2. IFNAR recruits proteins called STATs (Signal transducer and activator of transcriptions). The STATs are activated by phosphorylation.
   
3. pSTATs form homodimers (e.g. STAT1-STAT1) or heterodimers (e.g. STAT1-STAT2). 
4. pSTAT dimers enter the cell nucleus and bind to the DNA.
5. Transcription is blocked or reduced in some target genes (repression).
6. Transcription is activated in some target genes (expression).

 

Biological functions

• Immunity
  
• Antiviral responses
• Pro-inflammatory responses
  

 

Clinical significance

Disorders associated with IFNAR2 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
• Measles as a result of MMR vaccination
  
• Severe HHV6 infection
  
• Immunodeficiency 45 (IMD45)

These disorders suggest an increased susceptibility to severe viral infections, possibly due to an interferon signalling deficiency.

 

Protein profile

• Size (amino acids) = 515
• Molecular mass (Daltons) = 57,75
• Quaternary structure: Heterodimer with IFNAR1. Isoform 1 interacts with the transcriptional factors STAT1 and STAT2. IFNAR1 interacts with TYK2. IFNAR2 interacts with JAK1.
• Protein family: Cell surface receptor.

 

Genetic profile

• Species: Human
• Chromosome: 21
• Band: 21q22.11
• Starts at base pair: 33,229,901
• Ends at base pair: 33,265,675
• Sequence length (base pairs): 35,775
  

 

See also

• genecards.org
• Interferon
  

CCR2

Also known as

• C-C Chemokine Receptor Type 2
• C-C Motif Chemokine Receptor 2  
• CD192
• Cluster of differentiation 192
  
• Monocyte Chemoattractant Protein 1 Receptor
• Monocyte Chemotactic Protein 1 Receptor
  

 

Biological functions

• Immunity
  
• Antiviral responses
• Pro-inflammatory responses

 

Clinical significance

Disorders associated with CCR2 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
  

 

Protein profile

• Size (amino acids) = 374
  
• Molecular mass (Daltons) =  41,915
• Quaternary structure: Interacts with ARRB1. Interacts (via extracellular N-terminal region) with beta-defensin DEFB106A/DEFB106B. Interacts with NUP85; the interaction is required for CCR2 clusters formation on the cell membrane and CCR2 signaling.
  
• Protein family = Cell surface receptor.

 

Genetic profile

• Species: Human
• Chromosome: 3
• Band: 3p21.31
• Starts at base pair: 46,353,734
• Ends at base pair: 46,360,928
• Sequence length (base pairs): 7195

 

See also

• Chemokines 
• genecards.org

OAS1

Also known as

• 2'-5'-oligoadenylate synthetase 1

 

Laconic summary

• OAS1 is an enzyme. It promotes RNA degradation, to suppress viral infection.

 

Physiology

Upstream events:

• Expression of the OAS1 protein is induced by interferon signalling.
  
• OAS1 is activated by double-stranded RNA.
  

 

Molecular actions

• Activation of enzymes called RNASELs (latent ribonucleases).

 

Downstream outcomes:

• Degradation of host RNA within the cell. (Unavoidable consequence).
• Degradation of viral RNA within the cell. (Antiviral defence).
• Suppression of host protein synthesis. (Unavoidable consequence).
  
• Suppression of viral protein synthesis. (Antiviral defence).
  
• Suppression of viral RNA replication. (Antiviral defence).

 

Biological functions

• Suppression of viral replication.
  

 

Clinical significance

Disorders associated with OAS1 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology 
• Herpes simplex infection
• Yellow fever
• Infantile-onset pulmonary alveolar proteinosis hypogammaglobulinaemia
• Pulmonary alveolar proteinosis with hypogammaglobulinaemia
• Microphthalmia with limb anomalies

 

Protein profile

• Size (amino acids) = 400
  
• Molecular mass (Daltons) = 46,029
  
• Quaternary structure: Monomer. Homotetramer.
• Protein family = Enzyme. 2'-5'-oligoadenylate synthase.

 

Genetic profile

• Species: Human
• Chromosome: 12
• Band: 12q24.13
• Starts at base pair: 112,906,783
• Ends at base pair: 112,933,222
  
• Sequence length (base pairs): 26,439

 

See also

• genecards.org
• Interferon
  

DPP9

Also known as

• Dipeptidyl peptidase 9
• Dipeptidyl Peptidase-Like Protein 9
  

 

Physiology

Biological functions

• Cell adhesion

 

Clinical significance

Disorders associated with DPP9 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
• Idiopathic pulmonary fibrosis
• Chronic nasopharyngitis 
  

 

Protein profile

• Size (amino acids) = 863
  
• Molecular mass (Daltons) = 98,263
  
• Quaternary structure: Homodimer.
  
• Protein family: Enzyme > Serine protease
  

 

Genetic profile

• Species: Human
• Chromosome: 7
• Band: 7q36.2
• Starts at base pair: 153,887,097
• Ends at base pair: 154,894,285
• Sequence length (base pairs): 49,450

 

See also

• genecards.org
• DPP4 (Dipeptidyl peptidase-4)

Interferon

 System: Innate immune system

Laconic

Interferons are cytokines which are involved in anti-viral immunity.

 

Types

Type I interferons

• Signals

1. IFN-α
2. IFN-β
3. IFN-ε
4. IFN-κ 
5. IFN-ω

• Receptor = IFNAR
  
• IFNAR1
• IFNAR2

 

Type II interferons

• Signals

• IFNγ

• Receptor = IFNGR

1. IFNGR1
2. IFNGR2
   

 

Type III interferons

• Signals

1. IFN-λ1
2. IFN-λ2
3. IFN-λ3
4. IFN-λ4

• Receptors

1. IL10RB
   
2. IFNLR1
   

 

Downstream effects

• Upregulation of OAS1 => Activation of RNASELs (latent ribonucleases) => Degradation of viral (and host) RNA.
• Upregulation of PACT => Phosphorylation (activating) of PKR => Phosphorylation (deactivating) of eIF2α => Inhibition of viral (and host) protein synthesis.
• Upregulation of expression of major histocompatibility complex.
  

 

Biological functions

• Immune system modulation
• Anti-viral response
• Cancer suppression
  

 

See also

• Cytokines
• Leukocytes
• Lymphocytes
• Macrophages
• Natural killer cells
  
• Major histocompatibility complex
  

Cranial Nerve VI: Abducens Nerve

Organ system: The cranial nerves

Function

Motor

• Carries motor signals to the lateral rectus muscle. This is an extraocular muscle which draws the pupil of the eye outwards.

Cranial Nerve XII: Hypoglossal Nerve

Organ system: The cranial nerves

Function

Motor

• Carries motor signals to the extrinsic and intrinsic muscles of the tongue, with the exception of palatoglossus (innervated by the vagus nerve).
• Motor output during swallowing (alongside CN-IX and CN-X).

Cranial Nerve XI: Accessory Nerve

Organ system: The cranial nerves

Function

Motor

• Carries motor signals to the sternocleidomastoid muscles. This can turn rotate the head outwards.
• Carries motor signals to the trapezius muscles. This can elevate the pectoral girdle.

Cranial Nerve IV: Trochlear Nerve

Organ system: The cranial nerves

Function

Motor

• Carries motor signals to the superior oblique muscle. This is an extraocular muscle which draws the pupil of the eye downwards and rotates it outwards.

Cranial Nerve 0: Terminal Nerve

Organ system: The cranial nerves

Functions

Sensory

• Pheremone sensation during kissing or physical closeness
• Encouraging pair bonding between compatible healthy mates

Notes

• The existence of this cranial nerve is undisputed in various non-human species. In humans it is not universally recognised and it is poorly understood.
• It is possible that this structure is non-functional and vestigial. This could have atrophied alongside the olfactory system during human evolution. It could have been made redundant by the development of high intelligence and complex social behaviours.
• One reason for the lack of consesus is the difficulty in preserving and identifying this small structure during dissection.

 

See also

• Cranial Nerve I: Olfactory Nerve

Cranial Nerve VII: Facial Nerve

Organ system: The cranial nerves

Functions

Sensory

• Carrying taste sensation from the anterior 2/3 of tongue.

Motor

• Carrying motor signals to the muscles of facial expression 

 

Pathology

• Facial nerve diseases

Cranial Nerve IX: Glossopharyngeal Nerve

Organ system: The cranial nerves

Functions

Sensory

• Carrying taste sensation from the posterior 1/3 of tongue.   

Motor

• Motor output during swallowing (alongside CN-X and CN-XII).

Parasympathetic nervous system

Organ system: Autonomic nervous system

Function

• "Rest and digest"
• To reduce heart rate and stroke volume
• To dilate the capillaries, reduce peripheral vascular resistance, and decrease blood pressure
• To reduce respiratory rate
• To constrict the pupils (less light enters the retina)
• To promote gastrointestinal activity
• To initiate penile erection or vaginal tumescence

 

Mediators

• Cranial nerves: CN X (The vagus nerve)
• Spinal nerves: The pelvic splanchnic plexus

Sympathetic nervous system

Organ system: Autonomic nervous system

Function

• "Fight or flight"
• To increase heart rate and stroke volume
• To constrict the capillaries, raise peripheral vascular resistance and blood pressure
• To increase respiratory rate
• To inhibit gastrointestinal activity
• To dilate the pupils (more light enters the retina)
• To initiate ejaculation and orgasm

Somatic nervous system

 Organ system: Peripheral nervous system

Definition: The component of the peripheral nervous system which mediates transmission of information between the conscious mind and the body.

 

Functions

• Sensation of the external and internal enviroments and conscious perception of these sensations.
• Transmission of output from the central nervous system (e.g. voluntary motor commands) to the effector tissues (e.g. muscles)

Pathology 

• Paralysis
• Mononeuropathy
• Polyneuropathy
• Radiculopathy
• Allodynia
• Chronic pain
• Somatoform disorders

Autonomic nervous system

 Organ system: Peripheral nervous system

Definition: The component of the peripheral nervous system which carries involuntary, subconscious commands to the muscles and sweat glands of the body.

 

Divisions

By function

• Sympathetic nervous system
• Parasympathetic nervous system

By origin

• Cranial nerves
• Spinal nerves

The sympathetic and parasympathetic nerves are constantly transmitting signals (known as "sympathetic tone", "vagal tone", etc.) to maintain a dynamic balance in their target tissues. This 'tug of war' shifts towards sympathetic or parasympathetic effects as necessary.

Pathology

• Autonomic nervous system diseases

Removal of one system leaves the other system completely unopposed. For this reason, patients with spinal injuries may develop "autonomic dysfunction". Normal stimulation of the remaining system can cause life-threatening effects.

The spinal nerves

 Organ system: Peripheral nervous system

Features

• The spinal nerves originate from segments of the spinal cord.
• There is a pair of spinal nerve roots at each level in the vertebral column.

 

Cervical nerves

There are 7 cervical vertebrae in the spine.
Each spinal nerve pair arises above a cervical vertebra except C8, which arises below cervical vertebra C7.

• C1
• C2
• C3
• C4
• C5
• C6
• C7
• C8

 

Thoracic nerves

There are 12 thoracic vertebrae in the spine. 
Each spinal nerve pair arises below a thoracic vertebra.

• T1
• T2
• T3
• T4
• T5
• T6
• T7
• T8
• T9
• T10
• T11
• T12

 

Lumbar nerves

There are 5 lumbar vertebrae in the spine.
Each spinal nerve pair arises below a lumbar vertebra.

• L1
• L2
• L3
• L4
• L5

 

Sacral nerves

Along the sacrum the spinal nerve pairs arise through sacral foramina.

• S1
• S2
• S3
• S4
• S5

 

Coccygeal nerves

The final pair of spinal nerves are the coccygeal nerves.

• Co1

Compare with

• Cranial nerves

The cranial nerves

 Organ system: Peripheral nervous system

Features

• There are 12 well-known cranial nerves and 1 disputed cranial nerve (CN-0).
• The cranial nerves exist in symmetrical pairs.
• CN-0, CN-I, CN-II arise from the brain.
• CN-III to CN-XII (ten cranial nerves) arise from the brainstem.
• CN-II is not a peripheral nerve in the strictest sense, but it is technically a component of the CNS. This is because it is a rather a tract which outpouches from the diencephalon during embryonic development.

• CN 0 – Terminal
• CN I – Olfactory
• CN II – Optic
• CN III – Oculomotor
• CN IV – Trochlear
• CN V – Trigeminal
• CN VI – Abducens
• CN VII – Facial
• CN VIII – Vestibulocochlear
• CN IX – Glossopharyngeal
• CN X – Vagus
• CN XI – Accessory
• CN XII – Hypoglossal

Pathology

• Cranial nerve diseases

 

Compare with

• Spinal nerves

Cranial Nerve I: Olfactory Nerve

Organ system: The cranial nerves

Functions

Sensory

• Olfactory sensation from the nostrils in the nose.