Oxidized Cardiolipin as a Novel Pro-Inflammatory Factor

Abstract

Low levels of antibodies reactive with oxidised Cardiolipin (oxCL) in mammals are related to an increased risk of developing cardiovascular diseases, auto-immune diseases or inflammatory conditions. High levels can have a protective function and in general there is a negative association between manifestations of these conditions and antibodies against oxCL. Thus, based on their relations methods of monitoring, determining and diagnosing as well as methods of immunisation and therapy of these diseases and conditions are provided.

1 . A method for determining the risk of a mammal developing a cardiovascular disease, an auto-immune disease or inflammatory condition making use of oxidised cardiolipin (oxCL) or parts thereof and a marker of antibody-origin for binding to anti-oxCL/oxCL-complexes
 characterized in that the level of anti-oxCL in a sample of bodily fluid from said mammal is compared with a predetermined cutoff value for a given population of individuals of said mammal, said cutoff value being chosen to be 50% or less of the average level of anti-oxCL usually present in the population, so that concentrations of anti-oxCL lower than said cutoff value is associated with an increased risk of developing a cardiovascular disease, an auto-immune disease or inflammatory condition and concentrations of anti-oxCL higher than said cutoff value is not associated with an increased risk of developing a cardiovascular disease, an auto-immune disease or inflammatory condition.   
     
     
         2 . Method according to  claim 1  wherein said cut-off value is 35% or less of the average level of anti-oxCL usually present in the population. 
     
     
         3 . Method according to  claim 1  wherein said cardiovascular disease, auto-immune disease or inflammatory condition is/are selected from the group comprising cardiovascular disease, type II diabetes, Alzheimer's disease, dementia in general, rheumatic diseases, atherosclerosis, high blood pressure, acute and/or chronic inflammatory conditions, myocardial infarction (MI), acute coronary syndrome, stroke, transient ischemic attack (TIA), claudication, angina, type I diabetes, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), arthritis, idiopathic inflammatory myopathies (IIM), dermatomyositis (DM), polymyositis (PM), inclusion body myositis, an allergic disorder and/or osteoarthritis. 
     
     
         4 . The use of anti-oxCL in diagnostic in vitro methods as a diagnostic marker of mammal diseases wherein the level of anti-oxCL in a sample of bodily fluid from a given mammal is compared with a predetermined cutoff value for a given population of individuals of said mammal, said cutoff value being chosen to be 50% or less, of the average level of anti-oxCL usually present in the population, so that concentrations of anti-oxCL lower than said cutoff value is associated with an increased risk of developing a cardiovascular disease, an auto-immune disease or inflammatory condition and concentrations of anti-oxCL higher than said cutoff value is not associated with an increased risk of developing a cardiovascular disease, an auto-immune disease or inflammatory condition. 
     
     
         5 . Use according to  claim 4  wherein said cardiovascular disease, auto-immune disease or inflammatory condition is/are selected from the group comprising cardiovascular disease, diabetes II, Alzheimer's disease, dementia in general, rheumatic diseases, atherosclerosis, high blood pressure, acute and/or chronic inflammatory conditions, myocardial infarction (MI), acute coronary syndrome, stroke, transient ischemic attack (TIA), claudication, angina, type I diabetes, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPE)), arthritis, idiopathic inflammatory myopathies (IIM), dermatomyositis (DM), polymyositis (PM), inclusion body myositis, an allergic disorder and/or osteoarthritis. 
     
     
         6 . A kit for detecting the presence of anti-oxCL in a bodily fluid and for comparing the anti-oxCL concentration in said fluid with a predetermined cutoff value, said cutoff value being 50% or less, of the average level of anti-oxCL usually present in the population, so that concentrations of anti-oxCL lower than said cutoff value is associated with an increased risk of developing a cardiovascular disease, an auto-immune disease or inflammatory condition, and concentrations of anti-oxCL higher than said cutoff value is not associated with an increased risk of developing a cardiovascular disease, an auto-immune disease or inflammatory condition, said kit comprising
 A means for acquiring a quantity of the bodily fluid   A media having affixed thereto a capture antibody capable of complexing with anti-oxCL, and   an assay for the detection of a complex of the capture antibody and the anti-oxCL.   
     
     
         7 . A kit according to  claim 6  characterised in that the sample of bodily fluid can be characterised as a plasma, serum, blood, urine or saliva sample. 
     
     
         8 . Use of an agent that inhibits the activity of oxCL for the manufacture of a medicament for treating, preventing and/or reducing the risk of developing a cardiovascular disease, an auto-immune disease or inflammatory condition in a mammal wherein the agent that inhibits the activity of oxCL is selected from the group consisting of Annexin A5, or a monoclonal or polyclonal antibody of isotype IgA, IgD, IgE, IgG, IgM, raised against oxCL or bioactive components and/or parts/fragments thereof, optionally in combination with any suitable adjuvants, and wherein disease is selected from the group comprising cardiovascular disease, type II diabetes, Alzheimer's disease, dementia in general, rheumatic diseases, atherosclerosis, high blood pressure, acute and/or chronic inflammatory conditions, myocardial infarction (MI), acute coronary syndrome, stroke, transient ischemic attack (TIA), claudication, angina, type I diabetes, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), arthritis, idiopathic inflammatory myopathies (IIM), dermatomyositis (DM), polymyositis (PM), inclusion body myositis, an allergic disorder and/or osteoarthritis. 
     
     
         9 . An agent that inhibits the activity of oxCL for use in treating, preventing and/or reducing the risk of developing a cardiovascular disease, an auto-immune disease or inflammatory condition in a mammal, wherein the agent that inhibits the activity of oxCL is selected from the group consisting of Annexin A5, or a monoclonal or polyclonal antibody of isotype IgA, IgD, IgE, IgG, IgM, raised against oxCL or bioactive components and/or parts/fragments thereof, optionally in combination with any suitable adjuvants and wherein the disease is selected from the group comprising cardiovascular disease, type II diabetes, Alzheimer's disease, dementia in general, rheumatic diseases, atherosclerosis, high blood pressure, acute and/or chronic inflammatory conditions, myocardial infarction (MI), acute coronary syndrome, stroke, transient ischemic attack (TIA), claudication, angina, type I diabetes, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), arthritis, idiopathic inflammatory myopathies (IIM), dermatomyositis (DM), polymyositis (PM), inclusion body myositis, an allergic disorder and/or osteoarthritis, characterized in that the anti-oxCL concentration in a sample from the mammal to be treated is lower than a predetermined cutoff value, the cutoff value being chosen to be 50% or less of the average level of anti-oxCL usually present in the population of individuals of the mammal. 
     
     
         10 . Use of oxCL or bioactive components and/or parts/fragments thereof for the manufacture of a medicament for use in activation immunotherapy in the treatment, prevention and/or reduction of the risk of developing a cardiovascular disease, an auto-immune disease or inflammatory condition in a mammal wherein the disease is selected from the group comprising cardiovascular disease, type II diabetes, Alzheimer's disease, dementia in general, rheumatic diseases, atherosclerosis, high blood pressure, acute and/or chronic inflammatory conditions, myocardial infarction (MI), acute coronary syndrome, stroke, transient ischemic attack (TIA), claudication, angina, type I diabetes, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), arthritis, idiopathic inflammatory myopathies (IIM), dermatomyositis (DM), polymyositis (PM), inclusion body myositis, an allergic disorder and/or osteoarthritis, characterized in that the anti-oxCL concentration in a sample from the mammal to be treated with the medicament is lower than a predetermined cutoff value, the cutoff value being chosen to be 50% or less of the average level of anti-oxCL usually present in the population of individuals of the mammal. 
     
     
         11 . OxCL or bioactive components and/or parts/fragments thereof for use in activation immunotherapy in the treatment, prevention and/or reduction of the risk of developing a cardiovascular disease, an auto-immune disease or inflammatory condition in a mammal wherein the disease is selected from the group comprising cardiovascular disease, type II diabetes, Alzheimer's disease, dementia in general, rheumatic diseases, atherosclerosis, high blood pressure, acute and/or chronic inflammatory conditions, myocardial infarction, acute coronary syndrome, stroke, TIA, claudication, angina, type I diabetes, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), arthritis, idiopathic inflammatory myopathies (IIM), dermatomyositis (DM), polymyositis (PM), inclusion body myositis, an allergic disorder and/or osteoarthritis, characterized in that the anti-oxCL concentration in a sample from the mammal to be treated is lower than a predetermined cutoff value, the cutoff value being chosen to be 50% or less of the average level of anti-oxCL usually present in the population of individuals of the mammal. 
     
     
         12 . A method of treating, preventing or reducing the risk of developing a cardiovascular disease, an auto-immune disease or inflammatory condition in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of an agent that inhibits the activity of oxCL, wherein the agent that inhibits the activity of oxCL is selected from the group consisting of Annexin A5, or a monoclonal or polyclonal antibody of isotype IgA, IgD, IgE, IgG, IgM, raised against oxCL or bioactive components and/or parts/fragments thereof, optionally in combination with any suitable adjuvants and wherein the cardiovascular disease, auto-immune disease or inflammatory condition is/are selected from the group comprising cardiovascular disease, type II diabetes, Alzheimer's disease, dementia in general, rheumatic diseases, atherosclerosis, high blood pressure, acute and/or chronic inflammatory conditions, myocardial infarction (MI), acute coronary syndrome, stroke, transient ischemic attack (TIA), claudication, angina, type I diabetes, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Reiter's Syndrome, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), arthritis, idiopathic inflammatory myopathies (IIM), dermatomyositis (DM), polymyositis (PM), inclusion body myositis, an allergic disorder and/or osteoarthritis, characterized in that the anti-oxCL concentration in a sample from the mammal to be treated is lower than a predetermined cutoff value, the cutoff value being chosen to be 50% or less of the average level of anti-oxCL usually present in the population of individuals of the mammal. 
     
     
         13 . A method according to  claim 1 , characterized in that the sample of bodily fluid can be characterized as a plasma, serum, blood, urine or saliva sample. 
     
     
         14 . Use according to  claim 4  characterized in that the sample of bodily fluid can be characterized as a plasma, serum, blood, urine or saliva sample.