This report is the continuation of two earlier reports that defined human arterial intima and precursors of advanced atherosclerotic lesions in humans. This report describes the characteristic components and pathogenic mechanisms of the various advanced atherosclerotic lesions. These, with the earlier definitions of precursor lesions, led to the histological classification of human atherosclerotic lesions found in the second part of this report. The Committee on Vascular Lesions also attempted to correlate the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes. In the histological classification, lesions are designated by Roman numerals, which indicate the usual sequence of lesions progression. The initial (type I) lesion contains enough atherogenic lipoprotein to elicit an increase in macrophages and formation of scattered macrophage foam cells. As in subsequent lesion types, the changes are more marked in locations of arteries with adaptive intimal thickening. (Adaptive thickenings, which are present at constant locations in everyone from birth, do not obstruct the lumen and represent adaptations to local mechanical forces). Type II lesions consist primarily of layers of macrophage foam cells and lipid-laden smooth muscle cells and include lesions grossly designated as fatty streaks. Type III is the intermediate stage between type II and type IV (atheroma, a lesion that is potentially symptom-producing). In addition to the lipid-laden cells of type II, type III lesions contain scattered collections of extracellular lipid droplets and particles that disrupt the coherence of some intimal smooth muscle cells. This extracellular lipid is the immediate precursor of the larger, confluent, and more disruptive core of extracellular lipid that characterizes type IV lesions. Beginning around the fourth decade of life, lesions that usually have a lipid core may also contain thick layers of fibrous connective tissue (type V lesion) and/or fissure, hematoma, and thrombus (type VI lesion). Some type V lesions are largely calcified (type Vb), and some consist mainly of fibrous connective tissue and little or no accumulated lipid or calcium (type Vc).

A Definition of Advanced Types of Atherosclerotic Lesions and a Histological Classification of Atherosclerosis A Report From the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association

Prediction of the secondary structure of proteins from their amino acid sequence.

Avery never discussed the C-reactive protein without turning the conversation to what he was wont to call “the chemistry of the host.” Although he never spelled out what he meant by that expression, he clearly had in mind all the unidentified body substances and mechanisms of a nonimmunological nature, both protective and destructive, that come into play in the course of infectious processes.+ Rene J. Dubos

The phenomenon of the acute phase response

The compositions of lesion types that precede and that may initiate the development of advanced atherosclerotic lesions are described and the possible mechanisms of their development are reviewed. While advanced lesions involve disorganization of the intima and deformity of the artery, such changes are absent or minimal in their precursors. Advanced lesions are either overtly clinical or they predispose to the complications that cause ischemic episodes; precursors are silent and do not lead directly to complications. The precursors are arranged in a temporal sequence of three characteristic lesion types. Types I and II are generally the only lesion types found in children, although they may also occur in adults. Type I lesions represent the very initial changes and are recognized as an increase in the number of intimal macrophages and the appearance of macrophages filled with lipid droplets (foam cells). Type II lesions include the fatty streak lesion, the first grossly visible lesion, and are characterized by layers of macrophage foam cells and lipid droplets within intimal smooth muscle cells and minimal coarse-grained particles and heterogeneous droplets of extracellular lipid. Type III (intermediate) lesions are the morphological and chemical bridge between type II and advanced lesions. Type III lesions appear in some adaptive intimal thickenings (progression-prone locations) in young adults and are characterized by pools of extracellular lipid in addition to all the components of type II lesions.

A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.

Quantitative proteome profiling using stable isotope protein tagging and automated tandem mass spectrometry (MS/MS) is an emerging technology with great potential for the functional analysis of biological systems and for the detection of clinical diagnostic or prognostic marker proteins. Owing to the enormous complexity of proteomes, their comprehensive analysis is an as-yet-unresolved technical challenge. However, biologically or clinically important information can be obtained if specific, information-rich protein classes, or sub-proteomes, are isolated and analyzed. Glycosylation is the most common post-translational modification. Here we describe a method for the selective isolation, identification and quantification of peptides that contain N-linked carbohydrates. It is based on the conjugation of glycoproteins to a solid support using hydrazide chemistry, stable isotope labeling of glycopeptides and the specific release of formerly N-linked glycosylated peptides via peptide- N-glycosidase F (PNGase F). The recovered peptides are then identified and quantified by MS/MS. We applied the approach to the analysis of plasma membrane proteins and proteins contained in human blood serum.

Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry

A new form of amyloid protein associated with chronic hemodialysis was identified as β2-microglobulin

The present study was initiated in order to determine
the primary structures of the carbohydrate units of
desialyzed human plasma al-acid glycoprotein. In an earlier
investigation I6 glycopeptides which originated from four of
the five glycosylation sites of this protein were prepared in the
homogeneous state. Since the elucidation of the structures of
such a large number of carbohydrate units by the conventional
chemical and enzymatic procedures would require a very long
period of time and considerable amounts of material, a new
method-360-MHz H NMR spectroscopy-in combination
with methylation analysis and partial acetolysis was introduced
i n the present study. This highly sensitive method allowed the
elucidation of the structures of the carbohydrate units of the
mentioned glycopeptides to be carried out in a very short period of time. The present investigation revealed that the structures
of the 16 heteroglycans can be grouped into five classes, and,
except for those of two classes, the structures are new. Two
classes designated A and B possess the known bi- and trimtennary
structures, respectively. A third class designated C
proved to be tetraantennary in its structure, whereas the other
classes designated BF and CF are, in comparison with the
structures of classes B and C, characterized by an additional
fucose residue in a hitherto unknown position and linkage.
The latter monosaccharide residue is attached in an a( 1-3)
bond, vicinal to Gal@(1 +4), to the GlcNAc residue 7. The
present study also revealed that each glycosylation site of
pooled a]-acid glycoprotein possesses carbohydrate units with
different structures.

Determination of the primary structures of 16 asialo-carbohydrate units derived from human plasma alpha 1-acid glycoprotein by 360-MHZ 1H NMR spectroscopy and permethylation analysis.

Culture from mouse bone marrow of a subclass of mast cells possessing a distinct chondroitin sulfate proteoglycan with glycosaminoglycans rich in N-acetylgalactosamine-4,6-disulfate.

Structure of 1 -acid glycoprotein. The complete amino acid sequence, multiple amino acid substitutions, and homology with the immunoglobulins.

To study the relation between circulating immunosuppressive factors and anergy in patients with cancer, we tested 53 patients with cancer for hypersensitivity to skin-test antigens and 2,4-dinitrochlorobenzene. Of 41 patients with negative skin tests, 27 (66 per cent) had immunosuppressive serum (≥70 per cent inhibition of lymphocyte stimulation by phytohemagglutinin). None of 12 with positive skin tests had immunosuppressive serum. Thus, anergy and serum immunosuppressive activity were correlated (p<0.05). After ion-exchange chromatography, most of the immunosuppressive activity in cancer serum was in the first peak, fraction I. The same fraction from subjects without cancer contained no detectable immunosuppressive activity. Mean total immunosuppressive activity of cancer serum was 166.0 ± 97.5 (S.D.) units, and that of non-cancer serum was 30.4 ± 9.2 units (p<0.05). Diafiltration of fraction I. from cancer serum yielded a fraction (< 10,000 daltons) that was highly immunosuppressive. Thus, ane...

https://www.nejm.org/doi/pdf/10.1056/NEJM197412122912401?listPDF=true

Karl Schmid

Papers

A new form of amyloid protein associated with chronic hemodialysis was identified as β2-microglobulin

Determination of the primary structures of 16 asialo-carbohydrate units derived from human plasma alpha 1-acid glycoprotein by 360-MHZ 1H NMR spectroscopy and permethylation analysis.

Culture from mouse bone marrow of a subclass of mast cells possessing a distinct chondroitin sulfate proteoglycan with glycosaminoglycans rich in N-acetylgalactosamine-4,6-disulfate.

Structure of 1 -acid glycoprotein. The complete amino acid sequence, multiple amino acid substitutions, and homology with the immunoglobulins.

Association of Anergy with an Immunosuppressive Peptide Fraction in the Serum of Patients with Cancer