The Immune System and The Immune Disorders

The introduction of the
immune system started by studying structure and function of the immune system.
It is beneficial and it is very useful to study the introduction in detail. The
first session finished with good reading and revision of the components of the
immune system and how the body uses its innate and adaptive immune responses to
protect against microbial infections. It is very useful to increase my
knowledge about the structure of the lymph node and how they are functioning. The
second session increased my knowledge about the immune disorders and their mechanisms.
This session explained the immune system components are involved in physiological
and pathological processes.

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Now, I understood the
difference between innate and adaptive immune responses in the human. I also
understood the different immunological investigations involved in
immunodeficiency which was new to me.  I
have basic information about this topic and now this increased my knowledge and
understanding of the primary antibody deficiency diseases, secondary
immunodeficiency diseases, and complement disorders.


Gene therapy is an interesting and useful topic in the treatment
of inherited diseases that caused by various genes in order to correct
inherited gene defect. Different cases of genetic diseases were corrected using
gene therapy that can be used by transferring of targeted genes to somatic
cells of the patients in order to correct gene defect such as adenosine
deaminase deficiency. I learned about the investigations of primary antibody deficiencies
which could improve my understanding of these diseases and help biomedical
scientists to find and develop better and more effective immunodeficiency


I used some references which are very interesting and more
useful. I look forward to increasing my knowledge about immunodeficiency and
how we can benefit from it as a biomedical scientist in the diagnosis of
various diseases.


Key Questions: Critically
review the role of gene therapy in the treatment of primary
immunodeficiency diseases.


The inherited primary immunodeficiency, chronic granulomatous
disease (CGD), is caused by defects in the NADPH oxidase in neutrophilic granulocytes and monocytes.
This enzyme is responsible for the production
of reactive oxygen species (ROS). CGD is life-threatening due to infections
leading to inflammatory complications. To improve patient’s survival, antimicrobial
prophylaxis and antifungals can be used. Using hematopoietic stem cell
transplantation (HCT) and interferon
gamma (IFN-?) are other options for treatment. Transplantation can
improve the survival rates in children less than 10 years old.


Gene therapy is an alternative treatment option to transplant
in patients with no HLA identical donor. It is used to correct CD34+ gene of hematopoietic stem cells (HSCs). The gene
therapy was successful in all five patients by correcting the granulocytes that
can protect against severe infections. However, different trials with
retroviral and lentiviral vectors are limited because of stem cell toxicity and
transgene expression to the myeloid lineage. Genome editing approach using
zinc-finger nucleases (ZFN) and the clustered regularly interspaced short
palindromic repeat (CRISPR)-Cas9 system was used to allow gene correction in situ and they demonstrated
successful transgene expression in CD34+ HSCs and induced
pluripotent stem cells. Therefore, gene editing is promising to improve the safety and efficacy of gene
therapy in the future and may be a viable option for patients with primary
immunodeficiency diseases.


Lecture Topic:

(1)   The Role of Complement in Vascular Diseases

Blatt, A. Z., Saggu, G.,
Cortes, C., Herbert, A. P., Kavanagh D., Ricklin, D., John D. Lambris, J. D.,
and Ferreira, V. P. (2017), “Factor H C-Terminal Domains Are Critical for
Regulation of Platelet/Granulocyte Aggregate Formation”, Frontiers in Immunology, Vol. 8, pp. 1586. doi:  10.3389/fimmu.2017.01586.


The complement
alternative pathway (AP) is responsible for induction of the innate immune response
through activation of effector molecules and formation of the membrane attack
complex (MAC). Factor H (FH) is one of the main components of the complement system
and is responsible for AP regulation. It activates the C3/C5 convertases and
acts as a cofactor for Factor I-mediated cleavage of C3b. Factor H has binding
sites at the C-terminal domains, 19–20, which are used for interactions with
erythrocytes, platelets, endothelial cells, and neutrophils. Any mutation in
domains 19 and 20 will not bind to C3b and will lead to atypical hemolytic
uremic syndrome (aHUS), a prothrombotic disease. Platelet activation leads to
increased thrombi formation and then thrombocytopenia. Moreover, activated
platelets can also bind granulocytes to form platelet-granulocyte aggregates
(PGAs). The PGA formation may enhance vascular pathology in patients with acute coronary
syndromes, inflammatory bowel, lung disease, and diabetes. Thus, complement activation
receptor-activating peptide (TRAP) can induce PGA formation and AP activation on
platelets and neutrophils in the whole blood. Future investigations are
required to understand the pathophysiologic mechanisms involved in aHUS.


(2)   The Role of Innate Lymphoid Cells (ILCs) in
Autoimmune Diseases

S., Yang, D., Peng, T., Wu, Y., Tian, Z., and Ni, B. (2017), “Innate lymphoid
cell-derived cytokines in autoimmune diseases”, Journal of Autoimmunity, Vol. 83, pp. 62-72.


Innate lymphoid cells
(ILCs) are types of innate immune cells. They have similar functions with T
helper cells and cytotoxic CD8+ T lymphocytes. They are divided into
three groups according to their cytokines release, transcription factors, and
surface markers (group 1 ILCs produce interferon ?, group 2 ILCs produce IL-5 and
IL-13 and group 3 ILCs produce IL-17 and IL-22). ILCs have a great impact on the
immune response by participating in immunity, inflammation and tissue repair. The
dysregulated activation of ILCs can modulate immunity and contribute to
inflammation, allergies and autoimmune diseases. Recently, researchers found
that ILCs have a strong link with the pathogenesis of autoimmune diseases. Cytokines
secreted by group 1 and group 3 ILCs can promote inflammation in autoimmune
diseases whereas, cytokines secreted by group 2 ILCs can participate in
fibrosis of different tissues and organs. Therefore, targeting cytokines of
ILCs in therapy at the early stage of diseases is a promising strategy in many
conditions to modulate the immune response in different diseases.


(3)   The CRISPR/Cas9-Mediated Gene Editing is a Promising
Therapeutic Tool

Kim, E. J., Kang, K. H.
and Ju, J. H. (2017), “CRISPR-Cas9: a promising tool for gene editing on
induced pluripotent stem cells”, Korean
Journal of International Medicine, Vol. 32, no. 1, pp. 42–61.


Treatment of genetic
diseases can be approached through different methods. Recently, the clustered
regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated
nuclease 9 (Cas-9) technology is used as a promising tool in order to correct
genetic abnormalities and allow double-strand breaks (DSBs) formation that can
modify the gene expression. It is more accurate in genetic editing. This
technology has many applications in genetic diseases, induced pluripotent stem
cells, hemophilia, sickle-cell anemia, ?-thalassemia, human immunodeficiency
virus (HIV) and cancer research.  However,
ethical issues limit its uses in the modification of human embryos.


(4)   The Use of Immunoglobulin in Treatment of Primary

Krivan, G., Jolles, S.,
Granados, E. L., Paolantonacci, P., Ouaja, R., Cissé, O. A., and Bernatowska,
E. (2017), “New insights in the use of immunoglobulins for the
management of immune deficiency (PID) patients”, American Journal of Clinical and Experimental Immunology, Vol. 6,
no. 5, pp. 76-83.


(5)   The Uses of Measuring IgG Subclass in Diagnosis Primary
Antibody Deficiencies.

Parker, A. R., Skold, M.,
Ramsden, D. B., Ocejo-Vinyals, J. G., López-Hoyos, M., and Harding, S. (2017),
“The Clinical Utility of Measuring IgG Subclass Immunoglobulins
During Immunological Investigation for Suspected Primary
Antibody Deficiencies”, Laboratory
Medicine, Vol. 48, no. 4, pp. 314-325.



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