blau syndrome

Question 1

Describe autoinflammatory granulomatous diseases.

Answer 1

Autoinflammatory granulomatous diseases are a group of disorders characterized by recurrent episodes of inflammation and the formation of granulomas, which are collections of immune cells. These diseases often involve genetic mutations affecting the innate immune system.

Question 2

Define nosology in the context of autoinflammatory disorders.

Answer 2

In the context of autoinflammatory disorders, nosology refers to the classification and categorization of these clinical disorders characterized by recurrent episodes of fever and inflammation in different organs/tissues, which are caused by genetic variants of the innate immune system and mediated by cells of innate immunity, without the presence of autoantibodies and antigen-specific T cells.

Question 3

Describe the role of an antigen-present cell in the adaptive immune response.

Answer 3

Antigen-presenting cells capture and present antigens to T cells, initiating the adaptive immune response.

Question 4

Define auto-antibodies and their role in the immune system.

Answer 4

Auto-antibodies are antibodies that mistakenly target and attack the body’s own tissues, contributing to autoimmune diseases.

Question 5

Define autoimmunity and provide examples of diseases caused by autoantibodies.

Answer 5

Autoimmunity is the immune system’s attack on the body’s own tissues. Diseases caused by autoantibodies include autoimmune hemolytic anemia, systemic lupus, and myasthenia gravis.

Question 6

How do autoreactive T cells contribute to autoimmune diseases? Provide an example of a disease caused by autoreactive T cells.

Answer 6

Autoreactive T cells can directly attack the body’s own cells, leading to autoimmune diseases. An example of a disease caused by autoreactive T cells is insulin-dependent diabetes mellitus.

Question 7

Describe the role of pathogen-associated molecular patterns (PAMPs) in the innate immune response.

Answer 7

PAMPs are molecules associated with pathogens that can be recognized by the innate immune system, triggering an immune response.

Question 8

What is the function of NFkB signaling in the immune response?

Answer 8

NFkB signaling plays a crucial role in regulating the expression of genes involved in inflammation, immune responses, cell survival, and other physiological processes.

Question 9

How do chemokines contribute to the immune response?

Answer 9

Chemokines are a type of cytokine that act as chemoattractants, guiding the migration of immune cells to sites of infection or tissue damage during the immune response.

Question 10

Describe the activation of IFN and its role in causing diseases.

Answer 10

IFN activation can lead to diseases such as CANDLE and SAVI.

Question 11

autoinflammation :due to IL1: provide examples of clinical diseases it causes.

Answer 11

Autoinflammation can cause diseases like CAPS, FMF, HIDS, and TRAPS.

Question 12

How does increased NF-kB signaling contribute to diseases, and what are some examples of such diseases?

Answer 12

Increased NF-kB signaling can lead to diseases like Blau syndrome.

Question 13

Describe the composition of noncaseating epithelioid and giant cell granulomas.

Answer 13

They are organized aggregates of macrophages, epithelioid cells, multinucleated giant cells, and lymphocytes.

Question 14

Define the cause of noncaseating epithelioid and giant cell granulomas.

Answer 14

They result from an exaggerated immune-inflammatory response against an unidentified antigen who does not get degraded and can be associated with immune deficiencies, systemic vasculitides, and systemic inflammatory disorders.

Question 15

How are noncaseating epithelioid and giant cell granulomas associated with immune deficiencies and inflammatory disorders?

Answer 15

They can be associated with conditions such as chronic granulomatous disease (CGD), systemic vasculitides, and systemic inflammatory disorders like Crohn’s disease.

Question 16

Describe the importance of bacterial and fungal staining in the assessment of granulomatous infections.

Answer 16

Bacterial and fungal staining is crucial in the assessment of granulomatous infections to avoid initiating inappropriate therapies, such as corticosteroid or anti-tumor necrosis factor (TNF) therapy, in the presence of an ongoing infection.

Question 17

Describe the skin condition of the girl.

Answer 17

The girl has a monomorphic micropapular eruption, which appeared a few weeks after receiving the BCG vaccine. These are characterised by very dsicrete rashes

Question 18

What medical conditions did the girl’s father acquire?

Answer 18

The father acquired camptodactyly, chronic arthropathy, and visual acuity loss.

Question 19

Describe the clinical triad associated with Blau syndrome.

Answer 19

The clinical triad includes arthritis, uveitis, and rash, with early onset.
And histological finsing of non caseiting granuloma

Question 20

Define the inheritance pattern of Blau syndrome.

Answer 20

Blau syndrome has an autosomal dominant inheritance pattern, with familial occurrence.

Question 21

Describe Blau syndrome.

Answer 21

Blau syndrome is a rare genetic disorder characterized by the triad of granulomatous arthritis, uveitis, and dermatitis.

Question 22

Define CARD15/NOD2 mutations.

Answer 22

CARD15/NOD2 mutations are genetic variations in the CARD15 (also known as NOD2) gene, which have been associated with increased susceptibility to certain inflammatory disorders such as Blau syndrome.

Question 23

Define the clinical phenotype and disease course of Blau syndrome based on the study findings.

Answer 23

Blau syndrome is associated with severe ocular and articular morbidity, with visceral involvement being common and potentially life-threatening. Bone dysplastic changes may show diagnostic value.

Question 24

Do the study findings suggest any potential diagnostic value of bone dysplastic changes in Blau syndrome?

Answer 24

Yes, the study found that previously unknown dysplastic bony changes were found in two-thirds of patients, suggesting potential diagnostic value.

Question 25

What is the characteristic rash associated with Blau?

Answer 25

Reddish-brown micropapular rash followed by a tan-colored scaly ichthyosiform eruption.

Question 26

Describe the typical age of onset for granulomatous dermatitis in Blau syndrome.

Answer 26

Granulomatous dermatitis typically occurs within the first year of life.

Question 27

What is the weaning pattern of the rash in Blau syndrome?

Answer 27

The rash tends to wean with time.

Question 28

Describe the characteristics of the arthritis in the given content.

Answer 28

The arthritis is polyarticular, symmetrical, and affects both large and small peripheral joints. It is most predominant in the first decade and is associated with exuberant (teno)synovial swelling, relatively non-tender, and preserved range of motion.

Question 29

What are the typical features of joint involvement in the given content?

Answer 29

The joint involvement includes limitation, deformities (such as camptodactyly), and starts in the first decade. It affects both large and small peripheral joints and is polyarticular and symmetrical.

Question 30

Describe the clinical presentation of the patient in the Blau Syndrome cohort study.

Answer 30

The patient is a 27-year-old male with persistent rash, splenomegaly, synovitis in the right knee and wrists, camptodactyly, brachydactyly, and ankle and knee deformities.

Question 31

What are some of the key symptoms observed in the patient with Blau Syndrome in the cohort study?

Answer 31

The patient exhibited persistent rash, splenomegaly, synovitis in the right knee and wrists, camptodactyly, brachydactyly, and ankle and knee deformities.

Question 32

Define Blau Syndrome based on the clinical presentation of the patient in the cohort study.

Answer 32

Blau Syndrome is a rare genetic disorder characterized by the triad of granulomatous dermatitis, symmetric arthritis, and anterior uveitis, often accompanied by other systemic manifestations such as splenomegaly and camptodactyly.

Question 33

Describe the clinical manifestations in patients with NOD2 mutation.

Answer 33

The clinical manifestations in patients with NOD2 mutation include expanded features seen in one-third, with lung involvement as part of the Blau Registry Clinical Spectrum.

Question 34

Describe the association between NOD2 mutations and Blau syndrome.

Answer 34

NOD2 mutations, particularly those affecting R334, account for over 70% of reported Blau syndrome cases/families. These mutations are almost always located in or near the NACHT/NOD domain.

Question 35

Define somatic mosaicism in the context of Blau syndrome.

Answer 35

Somatic mosaicism in Blau syndrome refers to the presence of two or more genetically distinct cell populations in an individual, resulting in the manifestation of the complete triad phenotype.

Question 36

How do NOD2 mutations in Blau syndrome demonstrate incomplete penetrance?

Answer 36

Mutations affecting R334 account for 70% of reported cases

Certain NOD2 mutations, such as E383L and E383K, exhibit incomplete penetrance, meaning that not all individuals carrying these mutations will develop the complete triad phenotype associated with Blau syndrome.

Question 37

Define E600A (Glu600Ala) substitution in the context of familial granulomatous uveitis.

Answer 37

A specific genetic substitution found in seven family members with familial granulomatous uveitis.

Question 38

How does familial granulomatous uveitis typically manifest in affected individuals?

Answer 38

It presents with bilateral severe granulomatous panuveitis, usually appearing in late childhood or young adulthood, and without signs of arthritis or dermatitis.

Question 39

What are some key features of familial granulomatous uveitis?

Answer 39

It is characterized by bilateral severe granulomatous panuveitis, onset in late childhood/young adulthood, and the absence of arthritis or dermatitis.

Question 40

Do affected individuals with familial granulomatous uveitis typically show evidence of arthritis or dermatitis?

Answer 40

No, there is typically no evidence of arthritis or dermatitis in affected individuals with familial granulomatous uveitis.

Question 41

Describe the incomplete penetrance of the NOD2 mutation E383K in Blau syndrome.

Answer 41

The NOD2 mutation E383K in Blau syndrome shows incomplete penetrance, where some individuals with the mutation may not exhibit the associated symptoms.

Question 42

Describe the clinical presentation of the 17-year-old male mentioned in the content.

Answer 42

The patient presents with Blau triad dermatitis, uveitis, and oligoarthritis affecting large joints only, with no tenosynovitis.

the routihne test was negative so they looked at somatic NOD2 mosaicism

Question 43

What is the significance of the p.Arg334Gln NOD2 somatic mutation with variable frequencies in cells’ origin?

Answer 43

This mutation has been identified through targeted deep NOD2 sequencing of hematological/nonhematological tissues, with mutated allele frequencies varying across different cell types. It shows disruption of the inner domain interactions for conformational changes to active forms and basically facin-litate opening

Question 44

Define NOD2 and its role in the immune system.

Answer 44

NOD2 is a cytoplasmic pattern recognition receptor that plays a crucial role in recognizing bacterial components and initiating immune responses, particularly in the context of inflammatory signaling pathways.

Question 45

How does the NOD2 signaling pathway contribute to the immune response?

Answer 45

The NOD2 signaling pathway contributes to the immune response by activating downstream signaling molecules such as MAPKs, NF-kB, and IKK, leading to the production of inflammatory cytokines, chemokines, and the expression of target genes involved in immune regulation.

Question 46

Describe the relationship between NOD2 protein variants and constitutive NF-kB activation in cell culture transfection systems.

Answer 46

NOD2 protein variants are associated with constitutive NF-kB activation, particularly in the context of Blau syndrome (BS) versus Crohn’s disease (CD).

Question 47

What is the significance of the mutations identified in Japanese BS patients in relation to NF-kB activation?

Answer 47

The mutations identified in Japanese BS patients result in ligand-independent NF-kB activation in HEK293 cells transfected with NOD2 mutants.

Question 48

Define the relationship between early onset sarcoidosis (EOS) and CARD15 mutations causing constitutive NF-kB activation.

Answer 48

EOS is closely related to CARD15 mutations causing constitutive NF-kB activation, indicating a common genetic etiology with BS.

Question 49

How are sporadic EOS and familial BS related according to the findings?

Answer 49

The findings suggest that sporadic EOS and familial BS represent different types of the same juvenile systemic granulomatosis syndrome.

Question 50

Describe the role of NOD2 in inflammation and apoptosis.

Answer 50

NOD2 is an intracellular protein involved in inflammation and apoptosis, restricted to monocytes and capable of activating NF-kB.

Question 51

Define the association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease.

Answer 51

NOD2 leucine-rich repeat variants are associated with susceptibility to Crohn’s disease. Due to constitutive activation

Question 52

How does the NOD2 gene contribute to susceptibility to psoriatic arthritis?

Answer 52

The NOD2 gene, specifically the CARD15 variant, confers susceptibility to psoriatic arthritis as a pleiotropic autoimmune gene.

Question 53

Describe the process of immunistochemistry study of granulomas.

Answer 53

Immunohistochemistry study of granulomas involves analyzing the phenotype of lT helper ymphocytes, monocytes, and macrophages, as well as the presence of inflammatory cytokines, chemokines, and the expression of activation markers/apoptosis-related proteins. way less cytotoxic cells

you will find high IL6 and low TNF alpha

Question 54

Describe the morphology of Blau granulomas.

Answer 54

Blaugranulomas exhibit prominent lymphocytic coronas, internalisation of lymphocytes in MGCs, peri-and intragranulomatous fibrosis, and fibrinoid necrosis in the granuloma centre.

the core is of course macrophage

Histological finding will be very different from Blau to Caron patient with NOD2 SNP
Caron you see isolated granulomas, loose lymphocytic borders and sclerosis surrounding tissues

while for Blau HandE you will see granuloma complexes, prominent lymphocytic coronas and fibrinoid necrosis in the granuloma center

you see loads of Fas, FasL, BCL2 but no activated casp3

soooo activated macrophages are key players in NOD2 positive granuloma formation as well as CD4. TH17 axis is probably involved due to the cytokine expression pattern

Question 55

S100A12 and S100A8/9

Answer 55

biomarker for articular disease activity in Blau

it amplify the immune response. They are basically alarmins