1. Immune Disorders: HLA and Disease Associations and Amyloidosis
Nancy L. Jones, M.D.

2. Human Luekocyte Antigen Complex
Significance of HLA complex or MHC as a regulator of immune response
Bind peptide of foreign proteins for presentation to appropriate T cells know as MHC restriction
Chromosomes 6 and chromosome 15 for the β2-microglobulin
Highly polymorphic and presents a barrier to transplantation of organs

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6. HLA Class I antigens HLA-A , HLA-B, HLA-C each a heterodimer
Heavy α chain (44-kD) and smaller (12-kD)β2 micro globulin noncovalently associated with each other
Found on virtually all nucleated cells and platelets
Extracellular portion of α chain contains a cleft where foreign peptides bind to MHC molecules
Present foreign peptides to CD8+T cells (viral antigens processed within cell)
Cytotoxic T cell lysis of virus infected cells

7. Figure 6-9 The HLA complex and the structure of HLA molecules
Figure 6-9 The HLA complex and the structure of HLA molecules. A, The location of genes in the HLA complex is shown. The sizes and distances between genes are not to scale. B, Schematic diagrams and crystal structures of class I and class II HLA molecules. (Crystal structures are courtesy of Dr. P. Bjorkman, California Institute of Technology, Pasadena, CA.)
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8. HLA
Class II antigens
HLA-D with sub regions DP, DQ, and DR, each a heterodimer
Comprised of α and β subunits
Found on antigen presenting cells, macrophages and B cells
May be induced on endothelial cells, renal tubular epithelial cells and fibroblasts by IFN-α
Present foreign peptides to CD4+ T cells
(bacterial proteins synthesized outside cell) via the cleft in the extracellular portion
Cytokine mediated protective response

9. HLA Class III components of complement C2, C3 and Bf
Cytokines, TNF and lymphotoxin TNF-β also encoded at same site
DO NOT act as histocompatibility antigens
TNF is tumor necrosis factor

10. HLA
Six different class I HLA molecules expressed, three maternal and three paternal
(over 400 HLA-B alleles have been identified)
Can have over 20 different MHC II molecules
Amino acid sequence of peptide determines which MHC allele will bind a given peptide

11. HLA
Transplant rejection is the result of mismatched HLA haplotype, the combination of HLA alleles in each individual
Evokes humoral and cell mediated responses leading to graft destruction

12. HLA Genetic regulation of immune response
MHC has a role in T-cell stimulation
Can only bind and present antigen if the proper MHC molecules have been inherited
Type of immune response inherited and nature of antigen determine disposition to hypersensitivity reactions

13. HLA Many diseases are associate with particular HLA alleles
Inflammatory disease
Autoimmune diseases
Mechanisms of association are not understood at present

14. HLA Disease Associations Allele Disease Relative Risk
HLA-B27 Ankylosing Spondylitis %
HLA-B27 Postgonococcal arthritis 14
HLA-B27 Acute anterior uveitis 15
HLA-DR4 Rheumatoid arthritis 4
HLA-DR3 Autoimmune hepatitis 14
HLA-DR3 Primary Sjogren syndrome 10
HLA-DR3 Type 1 diabetes mellitus 5
HLA-DR4 “ 6
HLA-DR3/DR4 “ 15
Bw47 21-hydroxylase deficiency 15

15. Amyloidosis
A disorder characterized by extracellular deposition of mis-folded proteins that aggregate into insoluble fibrils
These deposition of these proteins may be due to excessive production of proteins prone to mis-folding and aggregation; mutations that produce proteins that cannot fold properly and tend to aggregate; or defective or incomplete proteolytic degradation of extracellular proteins

16. Pathogenesis of Amyloidosis
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17. Amyloidosis May be localized or systemic
Found in association with a variety of primary disorders including monoclonal B-cell proliferations where the amyloid deposits consist of immunoglobulin light chains; chronic inflammatory disorders such as rheumatoid arthritis with deposits of amyloid A protein derived from an acute-phase protein produced in inflammation

18. Amyloidosis
May be found in Alzheimer disease with deposition of amyloid β protein; in familial conditins in which the amyloid deposits consist of mutations of normal proteins such as transthyretin in familial amyloid polyneuropathies
Amyloidosis is associated with dialysis with deposits of β2-microglobulin, whose clearance is defective.

19. Amyloidosis
Amyloid deposits cause tissue injury and impair normal function by causing pressure on cells and tissues, but there is no inflammatory response to the deposits.

20. Amyloidosis
All amyloid has same morphology but is made up of many different proteins (up to 23 identified so far)
Deposits composed of nonbranching fibrils, 7.5 to 10 nm in diameter, formed of β-sheet polypeptide chains wound together.
Congo red binds to fibrils and produces a red-green birefringence.

21. Structure of amyloid fiber

22. Electron micrograph of amyloid fibrils

23. Histology of Amyloidosis
The deposition is always extracellular and begins between cells
Surrounds and destroys cells over time
Perivascular and vascular localizations are common in immunocyte-associated forms
Diagnosis based on staining characteristics
Congo red gives a pink or red color under ordinary light with polarization the amyloid shows apple-green birefringence

24. H&E stain of renal amyloid

25. Renal Amyloid congo red stain

26. Polarized congo red stain of renal amyloid

27. Gross Amyloid in the Kidney

28. Amyloid in spleen

29. Gross Amyloid in Spleen

30. Amyloid in the liver

31. Gross Amyloid in Liver

32. Cardiac Amyloidosis

33. Gross Amyloid in Heart

34. Amyloidosis Amyloid light chain protein (AL) produced by plasma cells
Complete Ig light chains, the amino-terminal fragment or both (monoclonal B-cell proliferations)
Amyloid associated fibril (AA)
Nonimmunoglobulin protein derived from 12-kD serum amyloid associated protein (SAA) made in the liver in chronic inflammatory states or in enzymatic defects
Aβ amyloid
a 4-kD peptide found in cerebral lesions of Alzheimer disease derived from amyloid precursor protein and larger gylcoprotein

35. Amyloidosis
Transthyretin (TTR) a normal serum protein that binds and transports thyroxine and retinol mutations lead to familial amyloid polyneuropathies. Found in hearts of the elderly (senile systemic amyloidosis)
Some familial amyloidosis is associated with deposits of mutant lysozyme

36. Amyloidosis
β2-microglobulin has been found as the amyloid fibril subunit (Aβ2m) in patients on long term dialysis
60-80% of patients on long term dialysis have deposits in synovium, joints and tendon sheaths
Procalcitonin and keratin have also been reported in amyloid deposits

37. Classification of Amyloidosis
Immunocyte Dyscrasias with Amyloidosis (Primary Amyloidosis)
Systemic
AL type
Most common form ~ 3000 cases/yr in US
Associated with multiple myeloma γ or κ light chains (Bence Jones proteins)
Patients with other underlying B-cell dyscrasias with increased plasma cells and immunoglobinopathy

38. Classification of Amyloidosis
Reactive Systemic Amyloidosis
Was previously called secondary amyloidosis
Systemic in distribution and composed of AA protein
Associated with chronic inflammatory states
Tuberculosis, bronchiectasis and chronic osteomyelitis
RA, ankylosing spondylitis and inflammatory bowel disease (autoimmune disorders)
“skin popping” with chronic infections
Renal cell carcinoma and Hodgkin lymphoma

39. Classification of Amyloidosis
Familial (Hereditary) Amyloidosis are rare and in limited geographic areas
Autosomal recessive familial Mediterranean fever
Armenians, Sephardic Jews and Arabs
Inflammation of serosal surfaces and synovial membrane
Gene produces pyrin which regulates acute inflammation
Autosomal dominant familial disorders with deposition of amyloid in peripheral and autonomic nerves known as amyloidotic polyneuropathies
Found in Portugal, Japan, Sweden, and the US
Fibrils are composed of mutant ATTRs.

40. Classification of Amyloidosis
Localized Amyloidosis
Single organ or tissue
Nodular masses which may be seen grossly
Lung, larynx, skin, urinary bladder, tongue and the region of the eye
Lymphocytes and plasma cells surround amyloid deposits are they the cause or a reaction?
One form involves AL protein
Microscopic lesions only

41. Classification of Amyloidosis
Endocrine Amyloid
Microscopic deposits found in endocrine tumors such as medullary carcinoma of the thyroid gland (derived from polypeptide hormones), islet tumors (islet amyloid polypeptide), pheochromocytomas and undifferentiated tumors of the stomach
Also found in Islets of Langerhans in type 2 diabetes

42. Classification of Amyloidosis
Amyloid of Aging
Senile systemic amyloidosis is a systemic deposition of amyloid in patients in their 70s or 80s
Dominant involvement and dysfunction of the heart presenting as a restrictive cardiomyopathy and arrhythmias
Amyloid is composed of normal TTR molecules
One form involves only the heart and is composed of a mutant TTR
4% of black population in US carry mutant allele and cardiomyopathy found in homozygous and heterozygous form

43. Amyloidosis Primary amyloidosis can lead to conditions that include:
Carpal tunnel syndrome dialysis patients
Cardiomyopathy leading to congestive heart failure
Intestinal malabsorption
Liver enlargement
Kidney failure and nephrotic syndrome
Neuropathy
Orthostatic hypotension

44. Amyloidosis Symptoms include: Abnormal heart rhythm Enlarged tongue
Fatigue
Numbness of hands and feet
Shortness of breath
Skin changes
Swallowing problems
Swelling in the arms and legs
Weak hand grip
Weight loss

45. Other symptoms include:
Decreased urine output
Diarrhea
Hoarseness or changes in the voice
Joint pain
weakness

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