This document summarizes the proposed mechanisms behind ankylosing spondylitis (AS), a type of arthritis that mainly affects the lower spine. It discusses how the presence of the HLA-B27 protein, found in over 95% of Caucasians with AS, may lead to inflammation through aberrant antigen processing and presentation. Specifically, mutations in HLA-B27 or the protein ERAP1, which helps cleave antigens for presentation, could cause immune responses through endoplasmic reticulum stress or inability to associate antigens with HLA-B27. Additional factors like the IL-23 pathway may also contribute to AS development. Genome-wide studies have identified other genetic loci associated with AS risk.
Definition:
Madura foot or mycetoma (tumour-like)
Chronic granulomatous disease characterised by localised infection of subcutaneous tissues and sometimes bone characterised by discharging sinuses filled with organisms like actinomycetes or fungi.
History:
Gill first described the disease in the Madura district of India in 1842.
Hence the term Madura foot.
Pathophysiology:Typically present in agricultural workers(hands shoulders and back – from carrying contaminated vegetation and other burdens).
Causes:Due to fungi – eumycetoma (40%) or
Actinomycetes – (actinomycetoma) 60%
Actinomycetoma may be due to Actinomadura madurae Actinomadura pelletieri Streptomyces somaliensis Nocardia species
Clinical Features:Slow spreading skin infection
Local swelling
Small hard painless nodules
Ulceration
Pus discharge
Scarred skin & discoloration
Itching
Pain and burning sensation
Lab studies:Direct microscopy
Blood – leukocytosis & neutrophilia
Culture of exudates
Skin biopsy
Serology
DNA sequencing has been used for identification in difficult cases.
Microscopy:Serosanguinous fluid containing the granules examined using – 10% KOH and Parker ink or calcofluor white mounts
Tissue sections stained using H&E(Hematoxylin and Eosin stain) , PAS(Periodic Acid Shiffs Stain) and Grocott’s methenamine silver(GMS).
Actinomycotic grains contains very fine filaments.
Fungal grains contain short hyphae (branched filaments) that are often swollen
Culture:Sabouraud’s dextrose agar or mycobiotic agar to isolate fungi
Blood agar to isolate bacteria
Agar plates are cultured at 25-30 degree celcius and 37 degree celcius for up to six weeks . Fungi grow more quickly than actinomycetes.
Treatment;Due to the slow ,relatively pain –free progression of the disease, mycetoma is often at an advanced stage when diagnosed.
Antifungals
Antibiotics
Treatment of any secondary infections
Amputation-in severe cases
Definition:
Madura foot or mycetoma (tumour-like)
Chronic granulomatous disease characterised by localised infection of subcutaneous tissues and sometimes bone characterised by discharging sinuses filled with organisms like actinomycetes or fungi.
History:
Gill first described the disease in the Madura district of India in 1842.
Hence the term Madura foot.
Pathophysiology:Typically present in agricultural workers(hands shoulders and back – from carrying contaminated vegetation and other burdens).
Causes:Due to fungi – eumycetoma (40%) or
Actinomycetes – (actinomycetoma) 60%
Actinomycetoma may be due to Actinomadura madurae Actinomadura pelletieri Streptomyces somaliensis Nocardia species
Clinical Features:Slow spreading skin infection
Local swelling
Small hard painless nodules
Ulceration
Pus discharge
Scarred skin & discoloration
Itching
Pain and burning sensation
Lab studies:Direct microscopy
Blood – leukocytosis & neutrophilia
Culture of exudates
Skin biopsy
Serology
DNA sequencing has been used for identification in difficult cases.
Microscopy:Serosanguinous fluid containing the granules examined using – 10% KOH and Parker ink or calcofluor white mounts
Tissue sections stained using H&E(Hematoxylin and Eosin stain) , PAS(Periodic Acid Shiffs Stain) and Grocott’s methenamine silver(GMS).
Actinomycotic grains contains very fine filaments.
Fungal grains contain short hyphae (branched filaments) that are often swollen
Culture:Sabouraud’s dextrose agar or mycobiotic agar to isolate fungi
Blood agar to isolate bacteria
Agar plates are cultured at 25-30 degree celcius and 37 degree celcius for up to six weeks . Fungi grow more quickly than actinomycetes.
Treatment;Due to the slow ,relatively pain –free progression of the disease, mycetoma is often at an advanced stage when diagnosed.
Antifungals
Antibiotics
Treatment of any secondary infections
Amputation-in severe cases
Avascular necrosis (AVN) of the femoral head is a pathologic process that results from interruption of blood supply to the bone. AVN of the hip is poorly understood, but this process is the final common pathway of traumatic or nontraumatic factors that compromise the already precarious circulation of the femoral head. Femoral head ischemia results in the death of marrow and osteocytes and usually results in the collapse of the necrotic segment
Knee effusion : Fluid Or Water On The Knee-Medical Studymartinshaji
To put it simply, effusion of the knee is the escape of fluid into the tissue. This occurs when excess fluid accumulates in or around the knee joint. A small amount of fluid naturally exists in normal joints, but when a joint is affected by arthritis, for example, abnormal amounts of fluid can build up causing the knee to become swollen around the top, outside and below your knee
this is a brief study on knee effusion
please comment
thank you/.............
Osteopenia refers to decreased bone mass.
Osteoporosis refers to osteopenia (reduced bone strength/mass) that is severe enough to increase the risk of fracture.
According to WHO, osteoporosis is defined as bone mineral density that falls 2.5 standard deviation below mean for young healthy adult of same sex and race.
Osteoporosis associated fractures :
These are adulthood fractures of any bones (chiefly hip and vertebral fractures) in the setting of trauma less than or equal to fall from standing height with exception of fingers, toes, face and skull.
Drugs associated with osteoporosis
Alcohol
Glucocorticoids
Anticoagulants
Anticonvulsants
Chemotherapy
Excess thyroxine
Endocrine disorders
Cushing syndrome
Hyperparathyroidism
Thyrotoxicosis
Diabetes mellitus (both type I and II)
Acromegaly
CATEGORIZATION OF OSTEOPOROSIS
A.Primary
Idiopathic
Postmenopausal
Senile/age related
B. Secondary (Diseases)
Hypogonadal state, endocrine disorders, nutritional and gastrointestinal disorders, rheumatologic disorders, hematological disorders/malignancy, inherited disorders and others.
Usually asymptomatic until fracture occurs
Vertebral and hip fracture common by simple fall
Loss of height due to multiple vertebral fracture and other deformities like lordoisis, kyphoscoliosis.
Fracture of femur neck, pelvis or spine causes deep vein thrombosis and pulmonary embolism, pneumonia.
INVESTIGATIONS FOR OSTEOPOROSIS
DXA (Dual energy X-ray absorptiometry)
Quantitative CT
Ultrasound
Urea, creatinine and electrolytes
Liver function test and albumin
Renal function test
Full blood count, ESR
Serum calcium and phosphate
Serum vitamin D and alkaline phosphate
Serum PTH
Thyroid function test
Testosterone, estrogen and gonadotropins
Serum cortisol
Bone biopsy
Plain radiography not diagnostic
Following non pharmacological approaches are taken:
Exercise
Appropriate calcium and vitamin D intake (Calcium 1000mg/day and vitamin D 800 IU/daily)
Cessation of smoking
Limit/ Quit alcohol intake
Get up and go exercise
Hip protectors to reduce the risk of fracture.
Pharmacological agents
Bisphosphonates ( decrease osteoclast activity)
Postmenopausal hormone replacement therapy
Denusumab (anti- RANKL antibody)
Anti- sclerostin antibodies
Cathepsin k antibodies
Avascular necrosis (AVN) of the femoral head is a pathologic process that results from interruption of blood supply to the bone. AVN of the hip is poorly understood, but this process is the final common pathway of traumatic or nontraumatic factors that compromise the already precarious circulation of the femoral head. Femoral head ischemia results in the death of marrow and osteocytes and usually results in the collapse of the necrotic segment
Knee effusion : Fluid Or Water On The Knee-Medical Studymartinshaji
To put it simply, effusion of the knee is the escape of fluid into the tissue. This occurs when excess fluid accumulates in or around the knee joint. A small amount of fluid naturally exists in normal joints, but when a joint is affected by arthritis, for example, abnormal amounts of fluid can build up causing the knee to become swollen around the top, outside and below your knee
this is a brief study on knee effusion
please comment
thank you/.............
Osteopenia refers to decreased bone mass.
Osteoporosis refers to osteopenia (reduced bone strength/mass) that is severe enough to increase the risk of fracture.
According to WHO, osteoporosis is defined as bone mineral density that falls 2.5 standard deviation below mean for young healthy adult of same sex and race.
Osteoporosis associated fractures :
These are adulthood fractures of any bones (chiefly hip and vertebral fractures) in the setting of trauma less than or equal to fall from standing height with exception of fingers, toes, face and skull.
Drugs associated with osteoporosis
Alcohol
Glucocorticoids
Anticoagulants
Anticonvulsants
Chemotherapy
Excess thyroxine
Endocrine disorders
Cushing syndrome
Hyperparathyroidism
Thyrotoxicosis
Diabetes mellitus (both type I and II)
Acromegaly
CATEGORIZATION OF OSTEOPOROSIS
A.Primary
Idiopathic
Postmenopausal
Senile/age related
B. Secondary (Diseases)
Hypogonadal state, endocrine disorders, nutritional and gastrointestinal disorders, rheumatologic disorders, hematological disorders/malignancy, inherited disorders and others.
Usually asymptomatic until fracture occurs
Vertebral and hip fracture common by simple fall
Loss of height due to multiple vertebral fracture and other deformities like lordoisis, kyphoscoliosis.
Fracture of femur neck, pelvis or spine causes deep vein thrombosis and pulmonary embolism, pneumonia.
INVESTIGATIONS FOR OSTEOPOROSIS
DXA (Dual energy X-ray absorptiometry)
Quantitative CT
Ultrasound
Urea, creatinine and electrolytes
Liver function test and albumin
Renal function test
Full blood count, ESR
Serum calcium and phosphate
Serum vitamin D and alkaline phosphate
Serum PTH
Thyroid function test
Testosterone, estrogen and gonadotropins
Serum cortisol
Bone biopsy
Plain radiography not diagnostic
Following non pharmacological approaches are taken:
Exercise
Appropriate calcium and vitamin D intake (Calcium 1000mg/day and vitamin D 800 IU/daily)
Cessation of smoking
Limit/ Quit alcohol intake
Get up and go exercise
Hip protectors to reduce the risk of fracture.
Pharmacological agents
Bisphosphonates ( decrease osteoclast activity)
Postmenopausal hormone replacement therapy
Denusumab (anti- RANKL antibody)
Anti- sclerostin antibodies
Cathepsin k antibodies
summary of factors contributing to the pathogeesis of SLE and the events that lead to its associated tissue damage, from genetic and immunologic point of view
Hemophagocytic lymphohistiocytosis (hlh), Langerhans cell histiocytosis dr vi...Vijitha A S
Hemophagocytic lymphohistiocytosis (hlh)
Langerhans cell histiocytosis,Benign proliferation of mature histiocytes and uncontrolled phagocytosis of the platelet, erythrocytes, lymphocytes, and their hematopoietic precursors in the bonemarrow & other tissues
Similar to Inflammatory effects of HLA-B27 as a Mechanism in Ankylosing Spondylitis (20)
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2. • Ankylosing Spondylitis
Overview
• Proposed Mechanism
• Roles of ERAP1 and HLA-B27
• Other Possible Causes
• Discovery of new AS-associated
loci
• Conclusion, Acknowledgements
3. What is Ankylosing Spondylitis?
• Arthritis that affects mainly the lower
vertebrae.
• Exact mechanism of the disease is
unknown
• Symptoms:
• Inflammation
• Soreness in lower back
• Stiffness in lower back
• Gastrointestinal irregularities
• Other areas that can be affected:
• Eyes
• Hips
• Ribs
• Lungs (rarely)
4. What we do know:
• Of the Caucasian population with a
confirmed diagnosis, >95% test positive
for Human Leukocyte Antigen – B27
(HLA-B27).
• This protein consists of 90 Amino Acids:
• GSHSMRYFHT SVSRPGRGEP RFITVGYVDD
TLFVRFDSDA ASPREEPRAP WIEQEGPEYW
DRETQICKAK AQTDREDLRT LLRYYNQSEA
• Most likely mechanism through which AS
operates is through an aberrant
processing of antigenic peptides.
5. Proposed Mechanism – What causes inflammation?
• HLA-B27 is one type of a major
histocompatibility complex that
presents antigens to CD8 lymphocytes
(T-cells) on the cell’s surface.
• Any type of mutation in the protein
can cause an aggregation of ‘unfit’
proteins in the Endoplasmic
Reticulum, which causes stress.
• The immune system responds by
generating pro-inflammatory cytokines
and chemokines.
6. Role of ERAP1
• ERAP1 serves as a ‘molecular ruler’ – it
cleaves proteins that have been partially
processed by the proteosome into
smaller peptides for association with
MHC class I proteins.
• MHC = Major Histocompatibility
Complex, AKA Human Leukocyte
Antigens (HLA’s).
• Single Nucleotide Polymorphs of ERAP1
can alter its efficiency, resulting in the
inability of peptides to associate with
HLA-B to be presented to the cell
surface.
• Shown Right: mean rate of cleavage of
N-Terminal Tryptophan residue in 10-
mer peptide, WRVYEKCALK, by ERAP1
Wild Type, and AS associated mutants. Evans, Spencer et al, 2011
7. Other possible causes of AS
• The IL-23 – IL-23R – IL-17 is also suspect
in the mechanism of AS.
• Studies have shown that an
overexpression of Tumor Necrosis Factor
Receptor 1 (TNFR1) is sufficient to
induce spondyloarthritis in mice.
• Further research is required to
determine if SNPs at the locus involved
in production of TNFR1 (12p13) are
associated with AS.
Iwakura and Ishigame, 2006
8. Discovery of new AS-associated loci
• SNPs at the RUNX3 loci may induce AS
through lowered CD8+ lymphocyte
counts
• RUNX3 is a key gene that encodes a
transcription factor involved in CD8+
lymphocyte differentiation
• CARD9, PTGER4
• CARD9 – mediates signals from
dectin-1 and -2, which are immunity
receptors for β-glucan. Mice treated
with higher amounts of β-glucan
developed spondyloarthritis.
• PGE2 acts through PTGER4 to
promote expansion of TH17 cell
counts (Evans et al, 2011).
9. Conclusion
• Most likely mechanism through with AS
develops is through an aberrant processing
of antigenic peptides, or their presentation
to CD8+ lymphocytes on the cell surface.
• HLA-B27 plays a predominant role in the
pathogenesis of the disease, but AS can still
develop even in cases in which HLA-B27 is
not present.
• Genes strongly associated with
pathogenesis of AS: IL23R, RUNX3, KIF21B,
2p15, IL12B, ERAP1, HLA-B, LBTR-TNFR1,
and 21q22 (Evans et al, 2011).
• Further 4 loci identified: ANTXR2, PTGER4,
CARD9, TBKBP1 (Evans et al, 2011).
10. Literature Cited
Evans, David M.; Spencer, Chris C A.; Pointon, Jennifer J.; Su, Zhan;
Harvey, David; Kochan, Grazyna; Oppermann, Udo; Dilthey, Alexander;
Pirinen, Matti; Stone, Millicent A; Appleton, Louise;
Moutsianas, Loukas; Leslie, Stephen; Wordsworth, Tom; Kenna, Tony J;
Karaderi, Tugce; Thomas, Gethin P; Ward, Michael M;
Weisman, Michael H; Farrar, Claire; Bradbury, Linda A; Danoy, Patrick;
Inman, Robert D; Maksymowych, Walter; Gladman, Dafna;
Rahman, Proton; Morgan, Ann; Marzo-Ortega, Helena; Bowness, Paul;
Gaffney, Karl; Gaston, J S Hill; Smith, Malcolm; Bruge-Armas, Jacome;
Couto, Ana-Rita; Sorrentino, Rosa; Paladini, Fabiana; Ferreira, Manuel
A; Xu, Huji; Liu, Yu; Jiang, Lei; Lopez-Larrea, Carlos; Diaz-Pena, Roberto;
Lopez-Vazquez, Antonio; Zayats, Tetyana; Band, Gavin;
Bellenguez, Celine; Blackburn, Hannah; Blackwell, Jenefer M.;
Bramon, Elvira; Bumpstead, Suzannah J.; Casas, Juan P.; Corvin, Aiden;
Craddock, Nicholas; Deloukas, Panos; Dronov, Serge;
Duncanson, Audrey; Edkins, Sarah; Freeman, Colin; Gillman, Matthew;
Gray, Emma; Gwilliam, Rhian; Hammond, Naomi; Hunt, Sarah E.;
Jankowski, Janusz; Jayakumar, Alagurevathi; Langford, Cordelia;
Liddle, Jennifer; Markus, Hugh S; Mathew, Christopher G.;
McCann, Owen T.; McCarthy, Mark I.; Palmer, Colin N A.;
Peltonen, Leena; Plomin, Robert; Potter, Simon C.; Rautanen, Anna;
Ravindrarajah, Radhi; Ricketts, Michelle; Samani, Nilesh;
Sawcer, Stephen J.; Strange, Amy; Trembath, Richard C.;
Viswanathan, Ananth C.; Waller, Matthew; Weston, Paul;
Whittaker, Pamela; Widaa, Sara; Wood, Nicholas W.; McVean, Gilean;
Reveille, John D.; Wordsworth, B Paul; Brown, Matthew A.;
Donnelly, Peter. 2011. “Interaction between ERAP1 and HLA-
B27 in ankylosing spondylitis implicates peptide handling
in the mechanism for HLA-B27 in disease susceptibility.”
Nature Genetics. Vol. 43:8. Pp 761-767.
Full length wild type ERAP1 was cloned into pFastBac as a C-terminal His-10 tagged fusion protein using standard cloning techniques. ERAP1 substitution mutants were generated using site-directed mutagenesis. Recombinant proteins were purified to homogeneity on affinity Ni-NTA, and purity was assessed using SDS-PAGE/Coomassie staining.Restriction of ERAP1 to HLA-B27 positive cases of AS is consistent with the disease model that aberrant trimming/presentation of antigenic peptides is involved in the pathogenesis of the disease.
SNP’s at 12p13 due to effects on Lymphotoxin Beta Receptor (LTBR), TNFR1, or both.
TH17 cells produce IL17, a pro-inflammatory cytokine that stimulates the production of other pro-inflammatory molecules.