The JAK-STAT system

There are 4 JAKs- JAK1, JAK2, JAK3 and TYK2. There are 7 STATs- STAT1,2,3,4 and 6, and 5a & 5b. JAKs and STATs pair as homodimers or heterodimers.

As the accompanying diagram from New England Journal of Medicine shows, JAKs activate STATs by phosphorylating them. The latter then translocate to the nucleus to affect DNA synthesis.

JAK3 and TYK2 are mainly involved in immunity. The others have pleiotropic functions.

Numerous cytokines act by activating the JAK receptors, and their cognate STATs as follows:

Interferon-gamma activates JAK1 & JAK2, leading to activation of STAT1.
Interferon alpha and interferon beta activate JAK1 and TYK2, which activates STAT1-STAT2.
IL-6, and IL-10 activate STAT-3.
Erythropoetin is considered a cytokine as it activates JAK2. This turns on STAT5a.
Growth hormone activates JAK2, which activates STAT5b.
The IL-2 common gamma chain, which is shared by IL-2, IL-4, IL-7, IL-9, IL-12 and IL-15, activates JAK1-JAK3, and thus STAT5b
IL-7 alpha chain is shared by IL-7 and Thymic Stromal Lymphopoetin. It activates JAK1-JAK3, and thus STAT5b.
STAT4 is activated by IL12 and IL23, via JAK2 & TYK2.
STAT6 is activated by IL-4 and IL-13. The intervening JAKs are not certain.

Three different conditions are associated with STAT1 mutations. Inactivating autosomal dominant mutations are associated with Mendelian Susceptibility to Mycobacterial Diseases (MSMD), a relatively mild condition. Such mutations reduce signalling from Interferon-gamma, which therefore reduces intra-macrophagic killing of tuberculous and non-tuberculous mycobacteria.

However, autosomal recessive mutations of STAT1 are more severe, as they reduce signalling from both interferon-gamma, and alpha and beta-interferons. Thus, there is increased vulnerability to both mycobacterial and viral infections, particularly with Herpes zoster. Such subjects die quite early in life of fulminant infections.

Autosomal recessive mutations can cause a less severe phenotype, which is compatible with longer survival.

Activating mutations of STAT1, on the other hand, lead to a completely different phenotype. These subjects suffer from chronic mucocutaneous candidiasis (CMCC), and can have cerebral aneurysms and scoliosis. These mutations act in a dominant fashion.

Why does an activating mutation of STAT1 lead to CMCC? This is because, a constitutively activated STAT1 inhibits the activation of STAT3 by the IL-6 family of cytokines. STAT3 is essential for the action of IL-17alpha, IL-17F, and IL-22, three very similar cytokines that are necessary to defend against fungal infections.

A similar situation is seen in inactivating mutations of STAT3. This led to the discovery of Hyper-IgE syndrome, also called Job's syndrome, which is characterised by very high levels of IgE, Staphylococcal lung infections with cyst formation and boils, cold abscesses of the skin, recurrent eczema, chronic mucocutaneous candidiasis (in common with activating mutations of STAT1), infections with dimorphic fungi such as Histoplasmosis, delay in eruption of permanent teeth, a peculiar facies and coronary aneurysms.

Hyper IgE syndrome is caused by dominant negative mutations in STAT3. A similar picture can be inherited recessively due to mutations in DOKC8.

It is thought that the phenotype is due to the loss of Th17 T cells, which secrete IL-17 alpha, IL-17F and IL-22. Loss of these cytokines predisposes to Staphylococcal and fungal infections.

While CMCC is seen in dominant activating mutations of STAT1, it can also be seen in a recessive condition- polyglandular autoimmune syndrome type 1, where there are circulating antibodies to IL-17 alpha and IL-17F, thus emphasising the role of IL-17 in this disorder.

A similar split between inactivating and activating mutations is seen in Wiskott-Aldrich syndrome, which is X-linked recessive and due to inactivating mutations. Activating mutations of the same gene leads to severe congenital neutropaenia.

Mutations of JAK2, specifically JAK2 V617F is the most well known abnormality of the JAK STAT pathway. It is observed in 95% of subjects with primary polycythemia and around 50% of subjects with primary myelofibrosis and essential thrombocythaemia.

Inactivating mutations of JAK3 can lead to Severe Combined Immunodeficiency, as it is the common pathway for 6 cytokines. Such subjects have poorly functioning T cells, normal B cells and defective NK cells, and require bone marrow transplantation to survive. Inactivating mutations of JAK3 was suspected to contribute to this phenotype when it became clear that the common gamma chain acted through JAK3. Prior to this, SCID had been thought to due to X-linked mutations of the common gamma chain only.

A less severe picture is seen with mutations of the IL-7 alpha chain. Although this affects T cell function, NK cells are spared as the main cytokine driving NK cell function is IL-15, which acts through the common gamma chain.

As expected, polymorphisms of STAT-6 leads to an allergic diathesis as it is activated by IL-4 and IL-13. Similarly, polymorphisms of STAT-4 leads to SLE & RA.

I'll discuss medications exploiting the JAK pathways in another post.