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)

ACE2

Also known as

• Angiotensin-converting enzyme 2

 

Laconic summary

• ACE2 is an enzyme involved in RAAS. Several viruses exploit it to enter host cells.

 

Physiology

• Catalyses the conversion of angiotensin II (a vasoconstrictor) into 'angiotensin 1-7' (a vasodilator).
• Lowers blood pressure.

See: Renin-Angiotensin-Aldosterone system (RAAS).

• Renin
  
• Angiotensin
• Angiotensinogen
  
• Angiotensin I
• Angiotensin II
• Angiotensin (1-7)
• Angiotensin-converting enzyme
• Aldosterone
  

Clinical significance

Pathogenicity

Exploited to facilitate entry into host cells, by pathogens:

• SARS-CoV2
• Coronavirus Disease 2019 (COVID-19)
  
• Pathophysiology
• SARS-CoV
• Severe Acute Respiratory Syndrome (SARS)
• HCoV-NL63
  

Related genetic disorders:

• Hartnup disorder

Related medications:

• Angiotensin Converting Enzyme Inhibitors (ACE-Is)
  
• Angiotensin Receptor Blockers (ARBs)

ACE2 is upregulated in patients who take ACE-i / ARB therapies.

New therapeutics

• Recombinant ACE2 may be an effective therapeutic in the management of Acute Respiratory Distress Syndrome.

 

Protein profile

• Size (amino acids) = 805
  
• Molecular mass (Daltons) = 92,463
  
• Quaternary structure: Homodimer.
• Protein family = Enzyme > Metalloenzyme (zinc-containing)
  

 

Genetic profile

• Species: Human
• Chromosome: X
• Band: Xp22.2
• Starts at base pair: 15,561,033
• Ends at base pair: 15,602,148
• Sequence length (base pairs): 41,116

 

See also

• genecards.org

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
  

Immunoglobulin light-chain amyloidosis

Disease class: Amyloidosis

Disease class: Paraproteinaemias  

Cryoglobulinaemia

Disease class: Haemostatic disorders

Disease class: Paraproteinaemias

Monoclonal Gammopathy of Undetermined Significance

Disease class: Hypergammaglobulinaemia
Disease class: Paraproteinaemias

Also known as

• MGUS

This refers to a plasma cell dyscrasia, in which abnormal excessive levels of gamma globulins are detected in the blood. There are no symptoms, but the patient has an increased risk of progression to malignancies such as multiple myeloma. One study found that the risk of progression to malignancy was 11% (6.5 times higher than the general population).

 

Monoclonal gammopathies

• Monoclonal Gammopathy of Undetermined Significance  
• Smouldering multiple myeloma
• Multiple myeloma

Hypergammaglobulinaemia

Disease class: Blood protein disorders
Disease class: Immunoproliferative disorders 

Types

• Mevalonate Kinase Deficiency 
• Monoclonal Gammopathy of Undetermined Significance 
• Smouldering multiple myeloma

Paraproteinaemias

Disease class: Blood protein disorders
Disease class: Immunoproliferative disorders 

Types

• Cryoglobulinaemia
• Heavy chain disease 
• Immunoglobulin light-chain amyloidosis
• Monoclonal Gammopathy of Undetermined Significance 
• Multiple myeloma
• POEMS syndrome
• Smouldering multiple myeloma
• Waldenstrom macroglobulinaemia

[Immunology] Introduction

Immunologists specialise in diseases of the immune system, including allergies. The spleen and bone marrow are closely associated with immunological diseases.
There is significant overlap with rheumatology, haematology, and medical genetics.
This is a pathology discipline.  

 

Etymology

Latin immūnis, immūnis, immūne = exempt, immune
Ancient Greek λογία (logia) = study

Immunology = the study of immunity (resistance against infectious diseases)

 

Subspecialties

• Allergy medicine / allergology

 

Investigations

 

History taking

 

Physical examination

 

Key presenting complaints, reasons for referral

• Allergic reactions (type 1 hypersensitivity)  
• Angioedema
• Anaphylaxis 
• Allergic contact dermatitis (type 4 hypersensitivity) 
• Frequent infections
• Rare or severe infections 

Immune system diseases 

Relevant diseases

• Atopy
• Asthma
• Allergic conjunctivitis 
• Atopic dermatitis (eczema)
• Allergic rhinitis (hay fever)
• Drug allergy
• Food allergy  
• Urticaria (hives) 
• Hypersensitivity
• Eosinophilic granulomatosis with polyangiitis 
• Granulomatosis with polyangiitis
• Hereditary angioedema
• Primary antibody deficiencies
• Hypogammaglobulinaemia
• Primary immunodeficiency disorders
• Autosomal recessive hyper-IgE syndrome
• X-linked Severe combined immunodeficiency (SCID)
• Wiskott-Aldrich syndrome
• Secondary immunodeficiency disorders

Angioedema

Disease class: Vascular diseases

Graft vs Host disease

Disease class: Immune system diseases

Immune reconstitution inflammatory syndrome

Disease class: Immune system diseases

Immunologic deficiency syndromes

Disease class: Immune system diseases

Types

• Agammaglobulinaemia
• Ataxia telangiectasia
• Common variable immunodeficiency
• Dysgammaglobulinaemia
• HIV infections
• Deltaretrovirus infections
• Leukocyte-adhesion deficiency syndrome
• Lymphopoenia
• Phagocyte bactericidal dysfunction
• Severe combined immunodeficiency 

This class includes all diseases caused by underactivity of the components of the immune system. 

Patients with these diseases have a significantly increased probability of severe or life-threatening infections. 

Immunoproliferative disorders

Disease class: Immune system diseases

Types

• Hypergammaglobulinaemia 
• Lymphoproliferative disorders 
• Paraproteinemias 

Lupus nephritis

Disease class: Glomerulonephritis

See also

• Systemic lupus erythematosus

DiGeorge syndrome