C A Wider Role for Hsp 60 in Autoimmunity

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1. Sequence Similarities Between Tissue-Specific Autoantigens and Hsp 60

We have also previously described a wide range of sequence similarities between human hsp 60 and other autoantigens (39). Many of the tissue-specific autoantigens are intracellular enzymes and others are structural proteins or membrane constituents. A comprehensive search of the protein sequence database identified extensive areas of amino acid similarity between a wide range of established autoantigens which are targets of an autoimmune response in a single disease and regions of human heat shock protein 60 (Table 2).

The expression of hsp 60 is increased under conditions of stress in many tissues. It has been proposed that a physiological function of this stress protein may be to alert the immune system to the presence of damaged cells and to function as a target for their removal (55). In autoimmune disease, the initial insult against the target cell may activate a population of cross-reactive T cells, which are then able to react with the homologous sequences on the tissue-spe-cific antigens. As the potential epitopes exhibit a variety of motifs, it would be expected that different MHC alleles would present alternative hsp 60 epitopes in the target cells, and thus susceptibility to specific autoimmune diseases would be associated with the expression of distinct MHC haplotypes. In the specific case of IDDM, the amino acid similarity between hsp 60 and the tissue-specific

Table 2 Regions of Similarity Between Human Hsp 60 and autoantigens

Hsp 60

Autoantigen

Similarity

K> M OD

region

Known autoantigen

region

score

Disease

1-7

Myelperoxidase

594-610

60

Glomerulonephritis

7-21

Cytochrome P-450

359-372

64

Chronic active hepatitis

7-21

17a-Hydroxylase

359-372

64

Addison's disease

12-32

Pyruvate dehydrogenase

18-36

62

Primary biliary cirrhosis

37^9

KU autoimmune antigen

81-93

63

Scleroderma

38-53

NADH dehydroreductase

45-63

62

Primary biliary cirrhosis

40-50

Cerebellar degeneration associated antigen

93-103

60

Paraneoplastic cerebellar degeneration

57-68

Cytochrome P-450

402-412

59

Chronic active hepatitis

65-75

Thyroglobulin

393-403

58

Hashimoto's thyroiditis

86-100

Cardiac myosin heavy chain

516-530

62

Coxsackie myocarditis

101-123

Cytokeratin

83-105

58

Rheumatoid arthritis

108-117

DNA-binding protein

73-82

58

Systemic lupus erythematosus

152-167

Bullous pemphigoid antigen

308-323

59

Pemphigoid

152-175

Neurofilament triplet M protein

727-749

67

Multiple sclerosis

202-221

Laminin p2 chain

1354-1375

61

Basement membrane

290-300

21-Hydroxylase

61-71

53

Addison's disease

328-339

Myelin-associated protein

286-297

60

Multiple sclerosis

329-345

Cytokeratin

34-50

62

Rheumatoid arthritis

354-374

Laminin p2 chain

205-225

60

Goodpasture's syndrome

384-396

Cardiac myosin heavy chain

136-148

65

Coxsackie myocarditis

o

391-405

Glutamic acid decarboxylase

520-534

56

Insulin-dependent diabetes

tu 3

432-450

Dihydrolipoamide dehydrogenase

70-88

57

Primary biliary cirrhosis

451-470

Cardiac myosin heavy chain

253-272

64

Coxsackie myocarditis

453-472

KU autoimmune antigen

192-212

60

Scleroderma

a >

468-480

Acetylcholine receptor

133-145

63

Myasthenia gravis

—*

492-502

KU autoimmune antigen

449-459

57

Scleroderma

w

552-572

Hsp 90

633-653

60

Systemic lupus erythematosus

o

562-571

Cytokeratin

545-554

81

Rheumatoid arthritis

3 CO

Source: From Ref. 39.

Source: From Ref. 39.

autoantigen GAD 65 covers a sequence of 15 residues, with 6 identities and 6 conserved substitutions (Table 3).

The identification of the primary epitope of GAD 65 in the NOD mouse provides support for this hypothesis (56). The initial T-cell proliferative response to a series of synthetic peptides which spanned the GAD 65 sequence was obtained with two overlapping peptides, with the conserved region corresponding to the sequence similarity with hsp 60 (Table 4). It would be of interest to determine whether this GAD 65 peptide-responsive T-cell population is also able to proliferate to the homologous hsp 60 peptide.

2. Common Epitope Motifs Between fi-Cell Autoantigens and Environmental Agents

In IDDM, epitope cross reactivity with an environmental agent which initiates P cell stress and hsp 60 upregulation may also be important. In a similar database search, we examined sequence homologies between hsp 60 and viral proteins. A further region of sequence homology between hsp 60 and GAD 65 was identified, which also showed a conserved motif with the nucleocapsid protein of coxsackie B4 virus. The homology between GAD 65 and the coxsackie sequence had been noted previously (57): however, the additional involvement of an hsp 60 epitope may also be of interest.

The epitope identified has been investigated as a target of both the humoral and cellular immune response in IDDM. Significantly increased antibody reactivity was identified to both the GAD 65 (PEVKEK) and hsp 60 (VEVNEK) peptides. In addition, the T-cell proliferative responses to extended PEVKEK peptides were significantly higher in a limited series of newly diagnosed patients with IDDM. However, the frequency of a positive response, with a stimulation index greater than 3, was not significantly higher, so the statistically significant difference reflects only weak proliferation to this peptide. This region does appear to be a key secondary epitope in the NOD mouse; in this animal model, the activation of the proliferative response is spontaneous, and it remains to be determined whether coxsackie infection or spontaneous loss of tolerance leads to activation of the cross-reactive epitope in human IDDM.

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