A Patient Makes Antibodies to Rejects the Treatment

choi

Gina Kolata, When the Body Rejects the Treatment; Patients often produce antibodies to drugs keeping them alive, sometimes to disastrous effect. New York Times, May 16, 2017.
https://www.nytimes.com/2017/05/ ... ntibodies.html?_r=0

Note:
(a) This report describe patients of Pompe Disease develops antibodies against the only treatment (a protein) available so far. So doctors decimates the immune system of patients.  

(b)
(i) In 1932 JC Pompe described the disease that now bears his name. See Joannes Cassianus Pompe
https://en.wikipedia.org/wiki/Joannes_Cassianus_Pompe
(1901-1945)
(ii) Pompe disease is glycogen storage disease type II.
(A) Patients of glycogen storage disease can not break down glycogen, lacking one or another enzyme needed to break down glycogen.
(B) Patients of Pompe disease lacks acid alpha glucosidase (also known as lysosomal alpha glucosidase).

* lysosome
https://en.wikipedia.org/wiki/Lysosome
(With a pH ranging from 4.5 to 5.0, the interior of the lysosomes is acidic compared to the slightly basic cytosol (pH 7.2) )
(C) glycoside hydrolase
https://en.wikipedia.org/wiki/Glycoside_hydrolase
(also called glycosidases; hydrolysis of glycosidic bonds [which is ether; see formula in this Wiki page])

choi

(c) The following is biochemistry 生物化学 (生化 for short). If you can not understand, skip it.
(i) All human sugar is D-form.  Take six-carbon glucose 葡萄糖 for example.  In nature, it exists in the equilibrium of a stick (straight; not cyclic) and cyclic form (consisting of a five-member, with the sixth carbon pointing up.  
(ii) An Englishman Norman Haworth shared the 1937 Nobel Prize in Chemistry. His way of depicting a cyclic glucose  is Haworth projection (which shows every atom (O, H and N) but not carbon, which is where the sticks of the ring meet). Search images.google.com with {Haworth projection glucose alpha  beta) -- no quotation marks -- and you will see that for D-glucose in cyclic form, the alpha and beta configurations are exactly, except that for carbon 1, where the -OH (called hydroxyl group in chemistry) in alpha configuration points DOWN -- whereas the same OH on carbon in beta configuration points UP.
(iii) Glycogen 肝糖 (produced and stored in liver and skeletal muscle 骨骼肌 in human)  and starch 淀粉 (of plants) are made of a myriad of (cyclic) D-glucose (hence, glucosides -- one of the many glycosides) which are linked together with alpha (1->4) glycosidic bond (between C1 of one glucose and and C4 of the next glucose to its right). Occasionally in both glycogen and starch, a glucose branched out with a alpha (1->6) glycosidic bond with another glucose. The difference between glycogen and starch is the former branching out about every 10 alpha (1->4) glycosidic bonds, but the latter, every 30 alpha (1->4) glycosidic bonds. Look in images.google.com.

Cellulose 纤维素 (which composes the cell wall of a plant) is made up of D-glucoses linked with beta (1->4) glycosidic bonds, and has to be hydrolyzed by cellulase 纤维酶, something humans do not have.  
(iv) In a glycogen storage disease (there are altogether 11 types), a patient lacks a specific enzyme to hydrolyze glycogen, which then accumulates with and kills cells. Starting with the most vulnerable cells types (in nerve or muscle).

(d) To treat Pompe disease, a patient receives the intravenous drips (cost: about ⅓ of a million dollars a year) of recombinant enzymes of acid alpha glucosidase: Myozyme and Lumizyme (identical but different brand names; both made by Genzyme).
(i) The problem is immune system of many patients considers the enzyme alien and attacks it (causing the medication to lose efficacy and/or anaphylactic shock (as in bee sting or penicillin shock) ).
(ii) This phenomenon is not surprising, in view of clonal selection (introduced by the Australian doctor Frank Macfarlane Burnet in 1957). The hypothesis, which turns out to be correct, states as follows. A human produces all kinds of B-lymphocytes, even against antigens 抗原 humans has never seen in history  (B stands for bursa, an organ in birds but not in mammals), each of which makes just one (specific) antibody, which are displayed on cellular surface of the B-lymphocyte.  All B-lymphocytes that recognize a self-antigen (an antigen of the host) will be eliminated (killed). When an alien antigen enters the host (from bacteria or viruses), some cells in the host tear down the antigen to a bite size, and presents the fragment (of the antigen) to a specific clone of B-lymphocytes, whose antibody and the fragment are a perfect match, like a key and a lock.  Nonetheless, most proteins (therefore antigens), such as acid alpha glucosidase, are WITHIN the cells of the host, which the immune system does not see and whose corresponding clones of antibodies-making B-lymphocytes were not eliminated in the infancy (in a bursa in birds, or in bone marrow in mammals; in both organs more B-lymphocytes are also formed). This is clonal deletion.

(e) Physicians have no way eliminating specific clones of B-lymphocytes that cause trouble by attacking DESIRABLE antigens. So they resort to killing B-lymphocytes, which have consequences -- eg, cancers down the road.